Materiały źródłowe

• #1 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8125314/

  Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. […] Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. […] Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. […] However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis.

• #2 Systemic Mastocytosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/203948-overview

  Systemic mastocytosis (systemic mast cell disease) is characterized by mast cell infiltration of skin and extracutaneous organs. Mast cells typically infiltrate the bone marrow and consequently affect the peripheral blood and coagulation system. Mast cells are derived from CD34+/ KIT+ pluripotent hematopoietic cells in the bone marrow. The neoplastic clones of mast cells express abnormal cell surface markers CD25 and/or CD2. […] More than 95% of adults with systemic mastocytosis have exon 17 KIT mutations, most commonly the KIT D816V mutation. This gain of function mutation in the KIT receptor was detected by polymerase chain reaction (PCR) techniques in 68% of bone marrow specimens in patients with systemic mastocytosis. Additional molecular aberrations are frequently identified in TET2, SRSF2, ASXL1, CBL, RUNX1, DNMT3A, and in the RAS pathway.

• #3 Systemic Mastocytosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544345/

  Systemic mastocytosis is an aggressive disorder characterized by the release of numerous vasoactive cell mediators due to excessive activity of mast cells, which results in a wide variety of symptoms. […] Systemic mastocytosis, in particular, is an aggressive form of the disorder characterized by the release of numerous vasoactive cell mediators due to excessive activity of mast cells, which can result in a wide variety of symptoms. […] The pathogenesis of all types of mastocytosis is the result of chronic and episodic discharge of mast cell mediators and excessive accumulation of mast cells in one or more tissues. Mast cells contain a range of vasoactive mediators and usually operate by releasing these chemicals to produce inflammatory reactions to safeguard the body from microbial invaders and other insults.

• #4 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8125314/

  Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. […] Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. […] Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. […] However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis.

• #5 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  New Insights into the Pathogenesis of Systemic Mastocytosis […] Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. Over 80% of patients with SM harbor the KIT D816V mutation. However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] New developments, including the use of next-generation sequencing (NGS) panels and the increasingly sensitive detection of the KIT D816V mutation have improved our understanding of SM pathogenesis. […] The identification of early cooperating events for KIT mutations may improve our understanding of the pathogenesis of SM, leading to more efficient treatments and improved outcomes for SM patients. […] An increasing body of data has indicated that other events (e.g., tropomyosin-related kinase [TRK]) may play important roles in the pathogenesis of mastocytosis. […] Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Collectively, these data suggested that TRKA signaling may improve neoplastic MC fitness, which would explain, at least in part, why the results of treatment with KIT inhibitors alone in SM patients have been disappointing in most studies. […] The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies.

• #6 Target Therapies for Systemic Mastocytosis: An Update

  https://www.mdpi.com/1424-8247/15/6/738

  Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MCs) in extra-cutaneous organs. It could be divided into indolent SM, smoldering SM, SM with an associated hematologic (non-MC lineage) neoplasm, aggressive SM, and mast cell leukemia. SM is generally associated with the presence of a gain-of-function somatic mutation in KIT at codon 816. […] More than 90% of SM patients harbor a somatic gain-of-function mutation in the KIT gene, namely KITD816V, that leads to a constitutional activity of the KIT receptor in a ligand-independent fashion. It has been demonstrated that SM cases with multilineage KIT mutation cluster more frequently with advanced mastocytosis (AdvSM) than indolent cases. […] The molecular mechanisms that underlie SM development are currently not well-understood. Over 80% of patients with SM harbor the gain-of-function mutation in codon 816 of the tyrosine kinase KIT, where valine is substituted for an aspartate (KITD816V mutation). Other less common (<5%) somatic KIT mutations identified in adult SM are V560G, D815K, D816Y, insVI815-816, D816F, D816H, and D820G.

• #7 Management of Advanced Systemic Mastocytosis: Clinical Challenges | JBM

  https://www.dovepress.com/management-of-advanced-systemic-mastocytosis-clinical-challenges-peer-reviewed-fulltext-article-JBM

  Systemic mastocytosis (SM) encompasses a diverse group of diseases involving neoplastic mast cells (MCs) that span a disease spectrum from indolent SM (ISM), which also includes a smoldering form (SSM), to an advanced form (AdvSM) that compromises life span. […] The molecular pathogenesis of SM is characterized in the majority of patients by a gain of function oncogenic mutation in the stem cell factor (SCF) transmembrane class III receptor KIT (CD117). […] Over 95% of patients with SM harbor mutations in exon 17 of the KIT gene involving an adenine to thymine base switch at nucleotide position 2468, which results in an aspartic acid-to-valine change at codon 816 (D816V). […] The functional consequence of this activation loop mutation is constitutive kinase activity leading to downstream signaling through MAPK, AKT, PI3K, and STAT signaling cascades.

• #8 Systemic mastocytosis: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/systemic-mastocytosis/

  Systemic mastocytosis occurs when white blood cells called mast cells, which are produced in bone marrow, abnormally accumulate in one or more tissues. In most cases of systemic mastocytosis, the accumulated mast cells have a mutation in a gene called KIT. The KIT gene provides instructions for making a protein that plays an important role in development and activity of mast cells. The KIT protein stimulates chemical signaling pathways that are involved in the growth and division (proliferation) of many types of cells, including mast cells. […] In systemic mastocytosis, mast cells most often accumulate in the bone marrow, which is where new blood cells are made. Mast cells can also gather in other tissues such as the gastrointestinal tract, lymph nodes, spleen, or liver. In severe cases, excessive accumulation of mast cells can interfere with normal organ functioning. Mast cells normally trigger inflammation during an allergic reaction. When mast cells are activated by an environmental trigger, they release proteins (called mediators) that signal an immune response. In systemic mastocytosis, excess mast cells mean more mediator proteins are being released in the tissues where the cells accumulate, leading to an increased immune response.

• #9 Systemic Mastocytosis

  https://www.aaaai.org/conditions-treatments/related-conditions/systemic-mastocytosis

  Mastocytosis is a disorder in which abnormal mast cells are increased in one or more organs. In this condition the growth of mast cells is poorly controlled, sometimes as the result of mutations that produce clones, or identical copies, of cells. The growth and replication of normal mast cells is controlled by a membrane protein named KIT, which can be regulated as a switch ON and OFF. Mutations in KIT that keep the switch ON are the cause of mastocytosis. The most common mutation, called KIT D816V, produces a receptor that is constantly activated resulting in continuous growth and activation of mast cells. […] Mastocytosis is categorized based on where the increased numbers of cells are found, the symptoms and clinical presentation, and findings on pathology. […] Most adults with systemic mastocytosis have infiltration of one or more internal organs with abnormal mast cells and can present with or without cutaneous mastocytosis.

• #10 Management of Advanced Systemic Mastocytosis: Clinical Challenges | JBM

  https://www.dovepress.com/management-of-advanced-systemic-mastocytosis-clinical-challenges-peer-reviewed-fulltext-article-JBM

  Systemic mastocytosis (SM) encompasses a diverse group of diseases involving neoplastic mast cells (MCs) that span a disease spectrum from indolent SM (ISM), which also includes a smoldering form (SSM), to an advanced form (AdvSM) that compromises life span. […] The molecular pathogenesis of SM is characterized in the majority of patients by a gain of function oncogenic mutation in the stem cell factor (SCF) transmembrane class III receptor KIT (CD117). […] Over 95% of patients with SM harbor mutations in exon 17 of the KIT gene involving an adenine to thymine base switch at nucleotide position 2468, which results in an aspartic acid-to-valine change at codon 816 (D816V). […] The functional consequence of this activation loop mutation is constitutive kinase activity leading to downstream signaling through MAPK, AKT, PI3K, and STAT signaling cascades.

• #11 Systemic Mastocytosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544345/

  Activating and inactivating mutations of KIT are implicated in the pathogenesis of systemic mastocytosis. […] The precise mechanism by which KIT-activating mutations improve signaling is not thoroughly understood, but these errors lead to stem cell factor (SCF)-independent activation. […] KITD816V is the most common driver mutation for systemic mastocytosis. […] KIT mutations are mostly somatic, so they don’t seem to be inherited although, they might be present at birth. […] FIP1L1-PDGFRA mutation is associated with eosinophilia. Other mutations, namely TET2, IgE, JAK2V617F, and RAS, have associations with systemic mastocytosis as well.

• #12 Target Therapies for Systemic Mastocytosis: An Update

  https://www.mdpi.com/1424-8247/15/6/738

  Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MCs) in extra-cutaneous organs. It could be divided into indolent SM, smoldering SM, SM with an associated hematologic (non-MC lineage) neoplasm, aggressive SM, and mast cell leukemia. SM is generally associated with the presence of a gain-of-function somatic mutation in KIT at codon 816. […] More than 90% of SM patients harbor a somatic gain-of-function mutation in the KIT gene, namely KITD816V, that leads to a constitutional activity of the KIT receptor in a ligand-independent fashion. It has been demonstrated that SM cases with multilineage KIT mutation cluster more frequently with advanced mastocytosis (AdvSM) than indolent cases. […] The molecular mechanisms that underlie SM development are currently not well-understood. Over 80% of patients with SM harbor the gain-of-function mutation in codon 816 of the tyrosine kinase KIT, where valine is substituted for an aspartate (KITD816V mutation). Other less common (<5%) somatic KIT mutations identified in adult SM are V560G, D815K, D816Y, insVI815-816, D816F, D816H, and D820G.

• #13 Systemic Mastocytosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544345/

  Activating and inactivating mutations of KIT are implicated in the pathogenesis of systemic mastocytosis. […] The precise mechanism by which KIT-activating mutations improve signaling is not thoroughly understood, but these errors lead to stem cell factor (SCF)-independent activation. […] KITD816V is the most common driver mutation for systemic mastocytosis. […] KIT mutations are mostly somatic, so they don’t seem to be inherited although, they might be present at birth. […] FIP1L1-PDGFRA mutation is associated with eosinophilia. Other mutations, namely TET2, IgE, JAK2V617F, and RAS, have associations with systemic mastocytosis as well.

• #14 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8125314/

  Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. […] Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. […] Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. […] However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis.

• #15 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8125314/

  New data suggested that KIT D816V is a late event in the pathogenesis of SM. […] Collectively, KIT mutations alone cannot explain the full clinical spectrum of SM. […] Moreover, the KIT D816V mutation burden does not correlate with clinical manifestations of ISM. […] An increasing body of data has indicated that other events (e.g., tropomyosin-related kinase [TRK]) may play important roles in the pathogenesis of mastocytosis. […] Interestingly, recent data have cumulatively suggested that the effects of constitutive KIT signaling are dependent on the developmental stage of the cell, targeted by the gain-of-function mutation. […] Taken together, these findings underscore the need to better understand SM pathogenesis for the development of more efficient treatment strategies. […] Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Identifying these genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is of the utmost importance for developing rationally targeted therapies.

• #16 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8125314/

  New data suggested that KIT D816V is a late event in the pathogenesis of SM. […] Collectively, KIT mutations alone cannot explain the full clinical spectrum of SM. […] Moreover, the KIT D816V mutation burden does not correlate with clinical manifestations of ISM. […] An increasing body of data has indicated that other events (e.g., tropomyosin-related kinase [TRK]) may play important roles in the pathogenesis of mastocytosis. […] Interestingly, recent data have cumulatively suggested that the effects of constitutive KIT signaling are dependent on the developmental stage of the cell, targeted by the gain-of-function mutation. […] Taken together, these findings underscore the need to better understand SM pathogenesis for the development of more efficient treatment strategies. […] Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Identifying these genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is of the utmost importance for developing rationally targeted therapies.

• #17

  https://haematologica.org/article/view/7840

  Systemic mastocytosis is a heterogeneous disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other organ organs/tissues. Mutations in KIT, most frequently KIT D816V, are detected in over 80% of all systemic mastocytosis patients. […] Recent studies have also revealed additional somatic defects (apart from mutations in KIT) in a majority of patients with advanced systemic mastocytosis. These include TET2, SRSF2, ASXL1, RUNX1, JAK2, and/or RAS mutations, which may adversely impact prognosis and survival in particular systemic mastocytosis with an associated hematological neoplasm. […] The presence of additional genetic defects in KIT D816V+ AdvSM patients may confer adverse prognosis as compared with patients without such abnormalities.

• #18 Target Therapies for Systemic Mastocytosis: An Update

  https://www.mdpi.com/1424-8247/15/6/738

  However, KIT mutations do not occur universally, and the question if individual mutations are sufficient to generate MC transformation and to explain alone the different clinical presentations of SM remains unsettled. KIT appears to be a weak oncogene and could represent a late event in the pathogenesis of mastocytosis. […] The currently favored mechanistic concept of AdvSM pathogenesis is of a multimutated neoplasm, in which mutations in TET2, SRSF2 and/or ASXL1 in a pluripotent hematopoietic precursor cell might precede the KITD816V mutation. The latter molecular alteration represents a “phenotype modifier” of clonal hematopoietic stem cell disorders for SM. […] The Mayo Alliance Prognostic System (MAPS) for SM developed a prognostic score in which the presence of adverse mutations (ASXL1/RUNX1/NRAS) was recognized as an independent risk factor. Similarly, the German registry-derived mutation-adjusted risk score for AdvSM (MARS) associated a worse OS with the number of concurrent mutations in the panel SRSF2/ASXL1/RUNX1.

• #19 Systemic Mastocytosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544345/

  Activating and inactivating mutations of KIT are implicated in the pathogenesis of systemic mastocytosis. […] The precise mechanism by which KIT-activating mutations improve signaling is not thoroughly understood, but these errors lead to stem cell factor (SCF)-independent activation. […] KITD816V is the most common driver mutation for systemic mastocytosis. […] KIT mutations are mostly somatic, so they don’t seem to be inherited although, they might be present at birth. […] FIP1L1-PDGFRA mutation is associated with eosinophilia. Other mutations, namely TET2, IgE, JAK2V617F, and RAS, have associations with systemic mastocytosis as well.

• #20

  https://haematologica.org/article/view/7840

  Systemic mastocytosis is a heterogeneous disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other organ organs/tissues. Mutations in KIT, most frequently KIT D816V, are detected in over 80% of all systemic mastocytosis patients. […] Recent studies have also revealed additional somatic defects (apart from mutations in KIT) in a majority of patients with advanced systemic mastocytosis. These include TET2, SRSF2, ASXL1, RUNX1, JAK2, and/or RAS mutations, which may adversely impact prognosis and survival in particular systemic mastocytosis with an associated hematological neoplasm. […] The presence of additional genetic defects in KIT D816V+ AdvSM patients may confer adverse prognosis as compared with patients without such abnormalities.

• #21

  https://www.ouhsc.edu/pathologyJTY/OUMC/OUMC-COM/Com05/Com509-1-Diss.htm

  The classification of systemic mast cell disease requires integration of clinical symptomatology, morphological assessment of the bone marrow, measurement of serum tryptase levels, and molecular/cytogenetic data. […] A well defined point mutation is present in the KIT gene in most patients with systemic mastocytosis. The most common mutation in systemic mast cell disease is an activating (gain of function) mutation in the KIT gene codon 816 (D816V). […] Interestingly, this mutation is in the tyrosine kinase domain and interferes with the binding of imatinib mesylate (Gleevac) to the enzymatic site of the Kit receptor protein, rendering these patients resistant to this drug. […] A second important cytogenetic alteration found in a subset of systemic mast cell disease patients is an interstitial deletion on Chromosome 4 which causes a fusion of the FIP1-like 1(FIP1L1) and PDGRFA proteins. […] Finally, in patients with associated clonal non-mast cell disorders, the bone marrow cytogenetics are usually characteristic of the non-mast cell disorder.

• #22

  https://haematologica.org/article/view/7840

  Systemic mastocytosis is a heterogeneous disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other organ organs/tissues. Mutations in KIT, most frequently KIT D816V, are detected in over 80% of all systemic mastocytosis patients. […] Recent studies have also revealed additional somatic defects (apart from mutations in KIT) in a majority of patients with advanced systemic mastocytosis. These include TET2, SRSF2, ASXL1, RUNX1, JAK2, and/or RAS mutations, which may adversely impact prognosis and survival in particular systemic mastocytosis with an associated hematological neoplasm. […] The presence of additional genetic defects in KIT D816V+ AdvSM patients may confer adverse prognosis as compared with patients without such abnormalities.

• #23 Target Therapies for Systemic Mastocytosis: An Update

  https://www.mdpi.com/1424-8247/15/6/738

  The impact of clonal architecture on responsiveness to midostaurin was explored in a group of 38 AdvSM patients. This study confirmed the negative prognostic impact of additional molecular aberrations in SRSF2, ASLX1, or RUNX1. ORR was significantly different between S/A/R negative (75%) and S/A/R positive (39%), in the same way, the median OS was 27 months for S/A/R positive patients and not reached for S/A/R negative patients.

• #24 Target Therapies for Systemic Mastocytosis: An Update

  https://www.mdpi.com/1424-8247/15/6/738

  However, KIT mutations do not occur universally, and the question if individual mutations are sufficient to generate MC transformation and to explain alone the different clinical presentations of SM remains unsettled. KIT appears to be a weak oncogene and could represent a late event in the pathogenesis of mastocytosis. […] The currently favored mechanistic concept of AdvSM pathogenesis is of a multimutated neoplasm, in which mutations in TET2, SRSF2 and/or ASXL1 in a pluripotent hematopoietic precursor cell might precede the KITD816V mutation. The latter molecular alteration represents a “phenotype modifier” of clonal hematopoietic stem cell disorders for SM. […] The Mayo Alliance Prognostic System (MAPS) for SM developed a prognostic score in which the presence of adverse mutations (ASXL1/RUNX1/NRAS) was recognized as an independent risk factor. Similarly, the German registry-derived mutation-adjusted risk score for AdvSM (MARS) associated a worse OS with the number of concurrent mutations in the panel SRSF2/ASXL1/RUNX1.

• #25 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8125314/

  New data suggested that KIT D816V is a late event in the pathogenesis of SM. […] Collectively, KIT mutations alone cannot explain the full clinical spectrum of SM. […] Moreover, the KIT D816V mutation burden does not correlate with clinical manifestations of ISM. […] An increasing body of data has indicated that other events (e.g., tropomyosin-related kinase [TRK]) may play important roles in the pathogenesis of mastocytosis. […] Interestingly, recent data have cumulatively suggested that the effects of constitutive KIT signaling are dependent on the developmental stage of the cell, targeted by the gain-of-function mutation. […] Taken together, these findings underscore the need to better understand SM pathogenesis for the development of more efficient treatment strategies. […] Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Identifying these genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is of the utmost importance for developing rationally targeted therapies.

• #26 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  New Insights into the Pathogenesis of Systemic Mastocytosis […] Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. Over 80% of patients with SM harbor the KIT D816V mutation. However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] New developments, including the use of next-generation sequencing (NGS) panels and the increasingly sensitive detection of the KIT D816V mutation have improved our understanding of SM pathogenesis. […] The identification of early cooperating events for KIT mutations may improve our understanding of the pathogenesis of SM, leading to more efficient treatments and improved outcomes for SM patients. […] An increasing body of data has indicated that other events (e.g., tropomyosin-related kinase [TRK]) may play important roles in the pathogenesis of mastocytosis. […] Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Collectively, these data suggested that TRKA signaling may improve neoplastic MC fitness, which would explain, at least in part, why the results of treatment with KIT inhibitors alone in SM patients have been disappointing in most studies. […] The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies.

• #27 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  New Insights into the Pathogenesis of Systemic Mastocytosis […] Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. Over 80% of patients with SM harbor the KIT D816V mutation. However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] New developments, including the use of next-generation sequencing (NGS) panels and the increasingly sensitive detection of the KIT D816V mutation have improved our understanding of SM pathogenesis. […] The identification of early cooperating events for KIT mutations may improve our understanding of the pathogenesis of SM, leading to more efficient treatments and improved outcomes for SM patients. […] An increasing body of data has indicated that other events (e.g., tropomyosin-related kinase [TRK]) may play important roles in the pathogenesis of mastocytosis. […] Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Collectively, these data suggested that TRKA signaling may improve neoplastic MC fitness, which would explain, at least in part, why the results of treatment with KIT inhibitors alone in SM patients have been disappointing in most studies. […] The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies.

• #28 Systemic Mastocytosis | Oncohema Key

  https://oncohemakey.com/systemic-mastocytosis-4/

  MCs retain surface KIT expression at high levels on maturation, and the interaction between the KIT and SCF has been shown to promote the proliferation, maturation, adhesion, chemotaxis, and survival of MCs. Consequently, gain-of-function mutations in KIT, particularly the D816V mutation, have been found to occur in most adult patients with SM, irrespective of WHO SM subtype. Other less common (5%) somatic KIT mutations identified in adult SM include V560G, D815K, D816Y, insVI815-816, D816F, D816H, and D820G. Recent studies have suggested that pediatric mastocytosis is also clonal in nature, and is associated with germline or acquired activating KIT mutations. […] The issue as to whether other genetic events, in addition to activating KIT mutations, are necessary for neoplastic transformation of MCs, and for full expression of the mastocytosis phenotype, remains to be clarified. This is illustrated by the divergent natural history of childhood-onset and adult-onset mastocytosis; although both are associated with activating KIT mutations, the former predominantly exhibits cutaneous-limited disease that spontaneously regresses with age In contrast, adult-onset mastocytosis is characterized by a persistent multiorgan involvement, often with a concurrent non-MC hematologic neoplasm.

• #29 Systemic Mastocytosis | Oncohema Key

  https://oncohemakey.com/systemic-mastocytosis-2/

  MCs retain surface KIT expression at high levels on maturation, and the interaction between the KIT and SCF has been shown to promote the proliferation, maturation, adhesion, chemotaxis, and survival of MCs. […] Consequently, gain-of-function mutations in KIT, particularly the D816V mutation, have been found to occur in most adult patients with SM, irrespective of WHO SM subtype. […] The issue as to whether other genetic events, in addition to activating KIT mutations, are necessary for neoplastic transformation of MCs, and for full expression of the mastocytosis phenotype, remains to be clarified. […] Recently, a high level of expression of microphthalmia-associated transcription factor (MITF), a transcription factor critical for MC development, was demonstrated in BM biopsy specimens from SM patients.

• #30 Systemic Mastocytosis | Oncohema Key

  https://oncohemakey.com/systemic-mastocytosis-2/

  These data suggest that MITF overexpression may be an important contributor to cell proliferation in mastocytosis and illustrate the role of additional genetic defects that may cooperate with KIT mutations in contributing to the fully transformed MC phenotype. […] Overall, the pathogenetic role and/or prognostic impact of TET2 mutations in SM currently remain unclear.

• #31 Systemic Mastocytosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/203948-overview

  Systemic mastocytosis (systemic mast cell disease) is characterized by mast cell infiltration of skin and extracutaneous organs. Mast cells typically infiltrate the bone marrow and consequently affect the peripheral blood and coagulation system. Mast cells are derived from CD34+/ KIT+ pluripotent hematopoietic cells in the bone marrow. The neoplastic clones of mast cells express abnormal cell surface markers CD25 and/or CD2. […] More than 95% of adults with systemic mastocytosis have exon 17 KIT mutations, most commonly the KIT D816V mutation. This gain of function mutation in the KIT receptor was detected by polymerase chain reaction (PCR) techniques in 68% of bone marrow specimens in patients with systemic mastocytosis. Additional molecular aberrations are frequently identified in TET2, SRSF2, ASXL1, CBL, RUNX1, DNMT3A, and in the RAS pathway.

• #32 Systemic Mastocytosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/203948-overview

  Systemic mastocytosis (systemic mast cell disease) is characterized by mast cell infiltration of skin and extracutaneous organs. Mast cells typically infiltrate the bone marrow and consequently affect the peripheral blood and coagulation system. Mast cells are derived from CD34+/ KIT+ pluripotent hematopoietic cells in the bone marrow. The neoplastic clones of mast cells express abnormal cell surface markers CD25 and/or CD2. […] More than 95% of adults with systemic mastocytosis have exon 17 KIT mutations, most commonly the KIT D816V mutation. This gain of function mutation in the KIT receptor was detected by polymerase chain reaction (PCR) techniques in 68% of bone marrow specimens in patients with systemic mastocytosis. Additional molecular aberrations are frequently identified in TET2, SRSF2, ASXL1, CBL, RUNX1, DNMT3A, and in the RAS pathway.

• #33 Rare diseases | Systemic Mastocytosis

  https://www.istitutogentili.com/en/rare-diseases/systemic-mastocytosis/

  Systemic mastocytosis (SM) is a rare disease resulting from the clonal expansion and accumulation of abnormal mast cells in various organs and tissues throughout the body. […] Mutations in the c-KIT gene activate the KIT receptor, even in the absence of its ligand. This mechanism: favours cell proliferation, reduces programmed cell death and, consequently, the accumulation of mast cells in certain organs and tissues of the human body. […] The treatment of systemic mastocytosis is tailored to the individual Patient based on: severity of the symptoms, manifestations of the disease, clinical evolution and prognosis. As there is no pharmacological treatment that is able to cure mastocytosis, the therapeutic options available have three aims: reduce the symptoms, by controlling the secretion and effects of mast cell mediators, reduce the extent of mast cell infiltration with cytoreduction therapies, treat the complications, such as organ dysfunction, caused by mast cell infiltration.

• #34

  https://www.scielo.br/j/spmj/a/7qTvTzbMkTNnkWYQyYzhQkL/

  Systemic mastocytosis is defined as a clonal disorder of mast cells and their precursor cells and is currently classified as a myeloproliferative neoplasm. […] Systemic mastocytosis encompasses a group of heterogeneous myeloproliferative neoplasms (MPNs) characterized by excessive proliferation of neoplastic MCs that accumulate in one or more organs, particularly in hematopoietic tissues. […] Abnormalities in SCF regulation or the c-kit receptor permanently affect the growth, differentiation, apoptosis and activation of mast cells. […] Activation of mutations of the c-kit receptor leads to pathological accumulation of mast cells in tissues as a result of clonal expansion and apoptotic defects. […] Several c-kit mutations have been reported in cases of systemic mastocytosis, although the most common one consists of substitution of valine for aspartate in codon 816 (Asp816Val), thus resulting in constitutive activation of the c-kit receptor.

• #35 Final Diagnosis — Case 366

  https://path.upmc.edu/cases/case366/dx.html

  Mastocytosis is a proliferation of mast cells and their subsequent accumulation in one or more organ systems. […] The pathogenesis of systemic mastocytosis is largely unknown. Activating mutations of the proto-oncogene c-kit tyrosine kinase receptor expressed by mature mast cells as well as an increased production of stem cell factor (SCF), the ligand for c-kit, have been implicated. […] A mutation affects codon 816 with the substitution of valine for aspartate (Asp816Val) in a putative activating loop in the kinase domain. This mutation at codon 816 is present in bone marrow mast cells in 80% of those with the disease. […] C-kit mutations are somatic mutations. Mast cells with mutated c-kit can grow and develop independent of exogenous cytokines. […] Disease manifestations result from a number of pathogenic mechanisms. These include increased numbers of mast cells in one or more tissues; local mass effects due to the mast cell accumulation; tissue response to cellular infiltrate; and local and distant effects of released mast cell mediators, such as histamine, eicosanoid, proteases, heparin, platelet-activating factor, cytokine and growth factor.

• #36 Central Role of Mast Cells in Mastocytosis, Hereditary α-Tryptasemia, Mast Cell Activation Syndrome, Urticaria, and Angioedema – European Medical Journal

  https://www.emjreviews.com/allergy-immunology/article/central-role-of-mast-cells-in-mastocytosis-hereditary-%CE%B1-tryptasemia-mast-cell-activation-syndrome-urticaria-and-angioedema-j01121/

  Mast cells are the central cells in the pathogenesis of many conditions that are associated with mediator release. […] Some conditions such as mastocytosis have a confirmed genetic background; however, the genetic background of hereditary -tryptasemia has only recently been described, and routine testing is yet to be set up in genetic laboratories. […] Systemic mastocytosis, in the World Health Organization (WHO) reclassification, represents a rare genetic disease, characterised by the activation of mast cells with aberrant proliferation, leading to multiorgan symptoms and, in some patients, severely debilitating symptom burden. […] Mast cell activation syndrome is a more prevalent, heterogeneous condition with an unclear aetiology, but has clinically similar symptoms associated with an impaired tolerance of mast cells.

• #37 Mastocytosis and Mast Cell Activation Syndrome – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/mastocytosis-and-mast-cell-activation-syndrome

  Mastocytosis is a group of disorders characterized by proliferation of mast cells and infiltration of the skin, other organs, or both. […] Pathology results mainly from release of mast cell mediators, including histamine, heparin, leukotrienes, and various inflammatory cytokines. […] Etiology in many cases of mastocytosis involves an activating mutation (D816V) in the gene coding for the stem cell factor receptor c-kit, which is present on mast cells. The result is autophosphorylation of the receptor, which causes uncontrolled mast cell proliferation. […] Systemic mastocytosis most commonly occurs in adults and is characterized by multifocal bone marrow lesions; it often involves other organs, most commonly skin, lymph nodes, liver, spleen, and/or gastrointestinal (GI) tract. […] Systemic mastocytosis is classified as indolent mastocytosis, with no organ dysfunction and a good prognosis; mastocytosis associated with other hematologic disorders (eg, myeloproliferative disorders, myelodysplasia, lymphoma); aggressive mastocytosis, characterized by impaired organ function; and mast cell leukemia, with 20% mast cells in bone marrow, no skin lesions, multiorgan failure, and a poor prognosis.

• #38 Systemic mastocytosis: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/systemic-mastocytosis/

  Systemic mastocytosis occurs when white blood cells called mast cells, which are produced in bone marrow, abnormally accumulate in one or more tissues. In most cases of systemic mastocytosis, the accumulated mast cells have a mutation in a gene called KIT. The KIT gene provides instructions for making a protein that plays an important role in development and activity of mast cells. The KIT protein stimulates chemical signaling pathways that are involved in the growth and division (proliferation) of many types of cells, including mast cells. […] In systemic mastocytosis, mast cells most often accumulate in the bone marrow, which is where new blood cells are made. Mast cells can also gather in other tissues such as the gastrointestinal tract, lymph nodes, spleen, or liver. In severe cases, excessive accumulation of mast cells can interfere with normal organ functioning. Mast cells normally trigger inflammation during an allergic reaction. When mast cells are activated by an environmental trigger, they release proteins (called mediators) that signal an immune response. In systemic mastocytosis, excess mast cells mean more mediator proteins are being released in the tissues where the cells accumulate, leading to an increased immune response.

• #39 Final Diagnosis — Case 366

  https://path.upmc.edu/cases/case366/dx.html

  Mastocytosis is a proliferation of mast cells and their subsequent accumulation in one or more organ systems. […] The pathogenesis of systemic mastocytosis is largely unknown. Activating mutations of the proto-oncogene c-kit tyrosine kinase receptor expressed by mature mast cells as well as an increased production of stem cell factor (SCF), the ligand for c-kit, have been implicated. […] A mutation affects codon 816 with the substitution of valine for aspartate (Asp816Val) in a putative activating loop in the kinase domain. This mutation at codon 816 is present in bone marrow mast cells in 80% of those with the disease. […] C-kit mutations are somatic mutations. Mast cells with mutated c-kit can grow and develop independent of exogenous cytokines. […] Disease manifestations result from a number of pathogenic mechanisms. These include increased numbers of mast cells in one or more tissues; local mass effects due to the mast cell accumulation; tissue response to cellular infiltrate; and local and distant effects of released mast cell mediators, such as histamine, eicosanoid, proteases, heparin, platelet-activating factor, cytokine and growth factor.

• #40 Skin and bones: systemic mastocytosis and bone in: Endocrinology, Diabetes & Metabolism Case Reports Volume 2023 Issue 2 (2023)

  https://edm.bioscientifica.com/view/journals/edm/2023/2/EDM22-0408.xml

  SM is recognised as a rare cause of secondary osteoporosis, whereby the release of mast cell mediators such as histamine, tryptase, heparin and interleukins may promote osteoclasts and inhibit osteoblasts, leading to bone resorption. […] There is a complex interplay between the balance of osteoclastic and osteoblastic drivers, and depending on disease manifestations, some patients may present with osteosclerosis rather than osteoporosis. […] Upon activation, mast cells secrete numerous mediators, either promoting osteoclastic (e.g. histamine, heparin, tumour necrosis factor, and interleukin-6) or inhibiting osteoblastic activity (e.g. interleukin-1, interleukin-6 and tumour necrosis factor). Conversely, mediators may also promote osteoblastic (e.g. transforming growth factor-) or inhibit osteoclastic activity (e.g. interleukin-12, interferon-) under different conditions.

• #41 Skin and bones: systemic mastocytosis and bone in: Endocrinology, Diabetes & Metabolism Case Reports Volume 2023 Issue 2 (2023)

  https://edm.bioscientifica.com/view/journals/edm/2023/2/EDM22-0408.xml

  SM is recognised as a rare cause of secondary osteoporosis, whereby the release of mast cell mediators such as histamine, tryptase, heparin and interleukins may promote osteoclasts and inhibit osteoblasts, leading to bone resorption. […] There is a complex interplay between the balance of osteoclastic and osteoblastic drivers, and depending on disease manifestations, some patients may present with osteosclerosis rather than osteoporosis. […] Upon activation, mast cells secrete numerous mediators, either promoting osteoclastic (e.g. histamine, heparin, tumour necrosis factor, and interleukin-6) or inhibiting osteoblastic activity (e.g. interleukin-1, interleukin-6 and tumour necrosis factor). Conversely, mediators may also promote osteoblastic (e.g. transforming growth factor-) or inhibit osteoclastic activity (e.g. interleukin-12, interferon-) under different conditions.

• #42 Skin and bones: systemic mastocytosis and bone in: Endocrinology, Diabetes & Metabolism Case Reports Volume 2023 Issue 2 (2023)

  https://edm.bioscientifica.com/view/journals/edm/2023/2/EDM22-0408.xml

  SM is recognised as a rare cause of secondary osteoporosis, whereby the release of mast cell mediators such as histamine, tryptase, heparin and interleukins may promote osteoclasts and inhibit osteoblasts, leading to bone resorption. […] There is a complex interplay between the balance of osteoclastic and osteoblastic drivers, and depending on disease manifestations, some patients may present with osteosclerosis rather than osteoporosis. […] Upon activation, mast cells secrete numerous mediators, either promoting osteoclastic (e.g. histamine, heparin, tumour necrosis factor, and interleukin-6) or inhibiting osteoblastic activity (e.g. interleukin-1, interleukin-6 and tumour necrosis factor). Conversely, mediators may also promote osteoblastic (e.g. transforming growth factor-) or inhibit osteoclastic activity (e.g. interleukin-12, interferon-) under different conditions.

• #43 Skin and bones: systemic mastocytosis and bone in: Endocrinology, Diabetes & Metabolism Case Reports Volume 2023 Issue 2 (2023)

  https://edm.bioscientifica.com/view/journals/edm/2023/2/EDM22-0408.xml

  Increase in osteoprotegerin and RANKL levels were also noted in SM, suggesting the involvement of the RANKL/RANK/OPG pathway. […] The prevalence of SM in patients with osteoporosis is unknown but is likely underdiagnosed. […] The prevalence of osteoporosis in SM ranges between 18 and 37%, and vertebral fractures affect up to 20% of patients. […] Thus, mediators favouring osteoclastogenesis may predominate with a moderate increase in mast cells, whereas mediators favouring osteoblastogenesis prevail with a higher mast cell burden. […] Studies have shown that while osteoporosis is a common feature in indolent SM, increased bone density is frequently encountered in advanced cases and associated with poorer prognosis. […] Predominance of osteoclastic activity and bone resorption is the driver of osteoporosis in patients with SM, and thus antiresorptive agents have been studied in its treatment. […] While denosumab appeared effective in reversing an initial decline in bone density, the dramatic improvement may also be related to the pro-osteoblastic effects of mediators associated with more advanced disease.

• #44 Skin and bones: systemic mastocytosis and bone in: Endocrinology, Diabetes & Metabolism Case Reports Volume 2023 Issue 2 (2023)

  https://edm.bioscientifica.com/view/journals/edm/2023/2/EDM22-0408.xml

  Increase in osteoprotegerin and RANKL levels were also noted in SM, suggesting the involvement of the RANKL/RANK/OPG pathway. […] The prevalence of SM in patients with osteoporosis is unknown but is likely underdiagnosed. […] The prevalence of osteoporosis in SM ranges between 18 and 37%, and vertebral fractures affect up to 20% of patients. […] Thus, mediators favouring osteoclastogenesis may predominate with a moderate increase in mast cells, whereas mediators favouring osteoblastogenesis prevail with a higher mast cell burden. […] Studies have shown that while osteoporosis is a common feature in indolent SM, increased bone density is frequently encountered in advanced cases and associated with poorer prognosis. […] Predominance of osteoclastic activity and bone resorption is the driver of osteoporosis in patients with SM, and thus antiresorptive agents have been studied in its treatment. […] While denosumab appeared effective in reversing an initial decline in bone density, the dramatic improvement may also be related to the pro-osteoblastic effects of mediators associated with more advanced disease.

• #45 The stromal composition of mast cell aggregates in systemic mastocytosis | Modern Pathology

  https://www.nature.com/articles/modpathol200953

  Systemic mastocytosis is a stem cell disorder characterized histologically by the presence of multifocal compact aggregates of mast cells in at least one extracutaneous organ with or without evidence of skin lesions. […] These findings indicate that systemic mastocytosis exhibits a distinct pattern of stromal change, and suggest that the fibrogenetic mechanism in systemic mastocytosis is most likely different from that of other bone marrow neoplasms which are also associated with fibrosis. […] The pattern of expression for these stromal markers is thus different from those observed in most cases of primary myelofibrosis and metastatic malignancy. […] In conclusion, the fibrotic lesions of systemic mastocytosis show abundant mature collagen, reduced vascularization as evidenced by scarce collagen IV, laminin, and CD34 expression, and the paucity of cells expressing low-affinity nerve growth factor receptor and stromal cells showing myofibroblastic differentiation. This pattern of stromal change is uncommonly seen in other bone marrow disorders characterized by fibrosis. […] These observations suggest that the pathogenetic mechanism leading to fibrosis in systemic mastocytosis may differ from that of other fibrotic neoplasms of the bone marrow.

• #46 The stromal composition of mast cell aggregates in systemic mastocytosis | Modern Pathology

  https://www.nature.com/articles/modpathol200953

  Systemic mastocytosis is a stem cell disorder characterized histologically by the presence of multifocal compact aggregates of mast cells in at least one extracutaneous organ with or without evidence of skin lesions. […] These findings indicate that systemic mastocytosis exhibits a distinct pattern of stromal change, and suggest that the fibrogenetic mechanism in systemic mastocytosis is most likely different from that of other bone marrow neoplasms which are also associated with fibrosis. […] The pattern of expression for these stromal markers is thus different from those observed in most cases of primary myelofibrosis and metastatic malignancy. […] In conclusion, the fibrotic lesions of systemic mastocytosis show abundant mature collagen, reduced vascularization as evidenced by scarce collagen IV, laminin, and CD34 expression, and the paucity of cells expressing low-affinity nerve growth factor receptor and stromal cells showing myofibroblastic differentiation. This pattern of stromal change is uncommonly seen in other bone marrow disorders characterized by fibrosis. […] These observations suggest that the pathogenetic mechanism leading to fibrosis in systemic mastocytosis may differ from that of other fibrotic neoplasms of the bone marrow.

• #47 Azthena logo with the word Azthena

  https://www.news-medical.net/health/What-is-Systemic-Mastocytosis.aspx

  Systemic mastocytosis is a myeloid neoplasm divided into six subcategories by the recent classification by WHO. It involves the accumulation of abnormal mast cells (MCs) in the skin, liver, spleen, and bone marrow. […] More than 90% of SM patients have a KIT D816V gain-of-function mutation. […] Systemic mastocytosis is usually linked to KIT somatic gain-of-function point mutations. […] The majority of adult SM patients have gain-of-function somatic mutations in the KIT tyrosine kinase domain, specifically the D816V mutation. […] Mutations produce a KIT protein that is always active. As a result, signaling pathways become hyperactive, resulting in increased mast cell production and accumulation.

• #48 Systemic mastocytosis: Determining the subtype of disease – UpToDate

  https://www.uptodate.com/contents/systemic-mastocytosis-determining-the-subtype-of-disease

  Mastocytosis describes a group of disorders in which pathologic mast cells accumulate in tissues. […] In systemic mastocytosis (SM), mast cells infiltrate extracutaneous tissues. […] Once the diagnosis of SM has been reached, the subtype (variant) of disease must be determined, as treatment and prognosis differ for each disorder.

• #49 Mastocytosis and Mast Cell Activation Syndrome – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/mastocytosis-and-mast-cell-activation-syndrome

  Mastocytosis is a group of disorders characterized by proliferation of mast cells and infiltration of the skin, other organs, or both. […] Pathology results mainly from release of mast cell mediators, including histamine, heparin, leukotrienes, and various inflammatory cytokines. […] Etiology in many cases of mastocytosis involves an activating mutation (D816V) in the gene coding for the stem cell factor receptor c-kit, which is present on mast cells. The result is autophosphorylation of the receptor, which causes uncontrolled mast cell proliferation. […] Systemic mastocytosis most commonly occurs in adults and is characterized by multifocal bone marrow lesions; it often involves other organs, most commonly skin, lymph nodes, liver, spleen, and/or gastrointestinal (GI) tract. […] Systemic mastocytosis is classified as indolent mastocytosis, with no organ dysfunction and a good prognosis; mastocytosis associated with other hematologic disorders (eg, myeloproliferative disorders, myelodysplasia, lymphoma); aggressive mastocytosis, characterized by impaired organ function; and mast cell leukemia, with 20% mast cells in bone marrow, no skin lesions, multiorgan failure, and a poor prognosis.

• #50 Systemic Mastocytosis

  https://www.aaaai.org/conditions-treatments/related-conditions/systemic-mastocytosis

  The diagnosis of systemic mastocytosis is determined by criteria established by the World Health Organization consensus group and requires meeting the major criterion plus one minor criterion or, alternatively, three of the minor criteria. […] In addition to the initial diagnosis, systemic mastocytosis is divided into subtypes determined by findings such as the amount of organ infiltration by mast cells (mast cell burden), presence or absence of other blood malignancies, and organ involvement with mast cell related damage such as enlarged liver, spleen or lymph nodes, or bone damage. […] Most adult patients fit into the indolent systemic mastocytosis category. […] Smoldering systemic mastocytosis patients have an inferior survival compared to indolent systemic mastocytosis, but the advanced age of those patients account for most of the difference.

• #51 SciELO Brazil – Systemic mastocytosis – a diagnostic challenge Systemic mastocytosis – a diagnostic challenge

  https://www.scielo.br/j/rbhh/a/9cLWWjdbqDkf5My4fVKzQdz/?lang=en

  Mastocytosis refers to a group of disorders characterized by the infiltration of clonally derived mast cells to the skin or extracutaneous tissues resulting in a heterogeneous clinical picture. […] Its molecular pathogenesis is incompletely understood. […] The molecular pathogenesis is incompletely understood but it is believed that activating mutations in the c-KIT receptor or CD117, essential for normal development and expansion of mast cells from hematopoietic progenitors, leads to a clonal hyperproliferation of atypical mast cells. The Asp816Val mutation is the most common. […] The diagnosis is histopathological and should include a bone marrow evaluation because, in most cases, infiltration occurs. […] After establishing the diagnosis it is necessary to define the disease category and the presence of B findings, corresponding to organ enlargement without organ dysfunction, or C findings that denote organ function impairment due to excessive mast cell infiltration; this latter is associated to a poorer prognosis.

• #52 Diagnostic Workup for Advanced Forms of Mastocytosis – TMS – The Mast Cell Disease Society, IncAccessibilityIncrease TextDecrease TextGrayscaleHigh ContrastNegative ContrastLight BackgroundLinks UnderlineReadable FontReset

  https://tmsforacure.org/expert-information/diagnostic-workup-advanced-forms-mastocytosis/

  C-findings (one is enough to diagnose aggressive SM) are indicative of ASM or MCL. […] It is of particular importance that organ damage caused by MC infiltration only counts as an SM-related C-finding. […] In case of suspected AHN, further markers and criteria to classify the AHN according to WHO criteria have to be applied to fully diagnose both the SM component and the AHN component of the disease and to identify potential drug targets. […] The most important molecular marker to show monoclonality in SM is the KIT point mutation D816V that can be analyzed in the bone marrow and the peripheral blood. […] In the majority of patients with SM, neoplastic MCs harbor this mutation. […] This suggests that additional genetic alterations, together with KIT D816V, result in neoplastic proliferation of MCs in advanced SM and thus are responsible for consecutive organ destruction by mast cell infiltration.

• #53

  https://scholars.duke.edu/display/pub804831

  Systemic mastocytosis (SM) is a heterogeneous disease with 6 subtypes, including systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease (SM-AHNMD). […] The pathogenesis of SM-AHNMD is not well understood; however, combined KIT tyrosine kinase receptor mutations and additional genetic events in myeloid stem cells may have a pathogenic role. […] Overall, the prognosis is poor and largely related to the AHNMD.

• #54

  https://scholars.duke.edu/display/pub804831

  Systemic mastocytosis (SM) is a heterogeneous disease with 6 subtypes, including systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease (SM-AHNMD). […] The pathogenesis of SM-AHNMD is not well understood; however, combined KIT tyrosine kinase receptor mutations and additional genetic events in myeloid stem cells may have a pathogenic role. […] Overall, the prognosis is poor and largely related to the AHNMD.

• #55 Educational theme | Systemic mastocytosis: Disease overview

  https://mpn-hub.com/medical-information/educational-theme-or-systemic-mastocytosis-disease-overview

  KITD816V mutations have been found in 90-95% of adult patients with SM. […] However, in pediatric patients, germline or acquired activating KIT mutations have been identified, and clinical manifestations are different. […] Whilst adults have persistent multiorgan involvement with a concurrent non-mast cell hematologic neoplasm, children exhibit disease which is limited to skin and regresses with age. […] TET2 and N-RAS mutations have also been shown to be associated with mastocytosis; however, the pathogenesis or any prognostic value has not yet been determined.

• #56 Educational theme | Systemic mastocytosis: Disease overview

  https://mpn-hub.com/medical-information/educational-theme-or-systemic-mastocytosis-disease-overview

  KITD816V mutations have been found in 90-95% of adult patients with SM. […] However, in pediatric patients, germline or acquired activating KIT mutations have been identified, and clinical manifestations are different. […] Whilst adults have persistent multiorgan involvement with a concurrent non-mast cell hematologic neoplasm, children exhibit disease which is limited to skin and regresses with age. […] TET2 and N-RAS mutations have also been shown to be associated with mastocytosis; however, the pathogenesis or any prognostic value has not yet been determined.

• #57 Educational theme | Systemic mastocytosis: Disease overview

  https://mpn-hub.com/medical-information/educational-theme-or-systemic-mastocytosis-disease-overview

  KITD816V mutations have been found in 90-95% of adult patients with SM. […] However, in pediatric patients, germline or acquired activating KIT mutations have been identified, and clinical manifestations are different. […] Whilst adults have persistent multiorgan involvement with a concurrent non-mast cell hematologic neoplasm, children exhibit disease which is limited to skin and regresses with age. […] TET2 and N-RAS mutations have also been shown to be associated with mastocytosis; however, the pathogenesis or any prognostic value has not yet been determined.

• #58 Systemic Mastocytosis

  https://www.aaaai.org/conditions-treatments/related-conditions/systemic-mastocytosis

  The diagnosis of systemic mastocytosis is determined by criteria established by the World Health Organization consensus group and requires meeting the major criterion plus one minor criterion or, alternatively, three of the minor criteria. […] In addition to the initial diagnosis, systemic mastocytosis is divided into subtypes determined by findings such as the amount of organ infiltration by mast cells (mast cell burden), presence or absence of other blood malignancies, and organ involvement with mast cell related damage such as enlarged liver, spleen or lymph nodes, or bone damage. […] Most adult patients fit into the indolent systemic mastocytosis category. […] Smoldering systemic mastocytosis patients have an inferior survival compared to indolent systemic mastocytosis, but the advanced age of those patients account for most of the difference.

• #59 Systemic mastocytosis – a diagnostic challenge | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-systemic-mastocytosis-diagnostic-challenge-articulo-resumen-S1516848414000048

  Mastocytosis refers to a group of disorders characterized by the infiltration of clonally derived mast cells to the skin or extracutaneous tissues resulting in a heterogeneous clinical picture. […] Its molecular pathogenesis is incompletely understood. […] The molecular pathogenesis is incompletely understood but it is believed that activating mutations in the c-KIT receptor or CD117, essential for normal development and expansion of mast cells from hematopoietic progenitors, leads to a clonal hyperproliferation of atypical mast cells. The Asp816Val mutation is the most common. […] The diagnosis is histopathological and should include a bone marrow evaluation because, in most cases, infiltration occurs. […] According to the WHO, diagnostic criteria for CM include skin lesions with compatible biopsy results, while for SM the presence of one major (multifocal clusters greater than 15 mast cells) and one minor criterion or three minor criteria (atypical morphology or spindle shapes in greater than 25% of the mast cells, c-KIT gene mutation, mast cells expressing the CD2 or CD25 surface markers or both, and increased serum tryptase levels greater than 20ng/mL) are required.

• #60 Systemic mastocytosis – a diagnostic challenge | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-systemic-mastocytosis-diagnostic-challenge-articulo-resumen-S1516848414000048

  Mastocytosis refers to a group of disorders characterized by the infiltration of clonally derived mast cells to the skin or extracutaneous tissues resulting in a heterogeneous clinical picture. […] Its molecular pathogenesis is incompletely understood. […] The molecular pathogenesis is incompletely understood but it is believed that activating mutations in the c-KIT receptor or CD117, essential for normal development and expansion of mast cells from hematopoietic progenitors, leads to a clonal hyperproliferation of atypical mast cells. The Asp816Val mutation is the most common. […] The diagnosis is histopathological and should include a bone marrow evaluation because, in most cases, infiltration occurs. […] According to the WHO, diagnostic criteria for CM include skin lesions with compatible biopsy results, while for SM the presence of one major (multifocal clusters greater than 15 mast cells) and one minor criterion or three minor criteria (atypical morphology or spindle shapes in greater than 25% of the mast cells, c-KIT gene mutation, mast cells expressing the CD2 or CD25 surface markers or both, and increased serum tryptase levels greater than 20ng/mL) are required.

• #61 Diagnosis and treatment of systemic mastocytosis in Brazil: Recommendations of a multidisciplinary expert panel | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-diagnosis-treatment-systemic-mastocytosis-in-articulo-S2531137922000803

  The presence of atypical morphology in more than 25% of the MCs, including spindle-shaped MCs, is considered a minor criterion. […] Most patients with systemic mastocytosis harbor mutations in the KIT gene, which encodes the stem cell factor receptor CD117, a class III receptor tyrosine kinase expressed by MCs, hematopoietic progenitor cells, germ cells, melanocytes and interstitial cells of Cajal in the gastrointestinal tract. […] The gain-of-function D816V mutation in the KIT gene is detected in most ( 95%) adult patients with SM. […] The D816V KIT mutation allele burden was also found to correlate with disease activity, disease subtype and survival. […] Analysis of KIT mutations in bone marrow cells is a standard diagnostic procedure for SM. […] The sensitivity of the KIT mutation testing for the SM diagnosis may be enhanced by enriching the sample for neoplastic MCs by laser capture microdissection, magnetic bead-based, FACS-based cell sorting, or using digital/allele-specific PCR techniques with high sensitivity.

• #62 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8125314/

  New data suggested that KIT D816V is a late event in the pathogenesis of SM. […] Collectively, KIT mutations alone cannot explain the full clinical spectrum of SM. […] Moreover, the KIT D816V mutation burden does not correlate with clinical manifestations of ISM. […] An increasing body of data has indicated that other events (e.g., tropomyosin-related kinase [TRK]) may play important roles in the pathogenesis of mastocytosis. […] Interestingly, recent data have cumulatively suggested that the effects of constitutive KIT signaling are dependent on the developmental stage of the cell, targeted by the gain-of-function mutation. […] Taken together, these findings underscore the need to better understand SM pathogenesis for the development of more efficient treatment strategies. […] Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Identifying these genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is of the utmost importance for developing rationally targeted therapies.

• #63 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  New Insights into the Pathogenesis of Systemic Mastocytosis […] Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. Over 80% of patients with SM harbor the KIT D816V mutation. However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] New developments, including the use of next-generation sequencing (NGS) panels and the increasingly sensitive detection of the KIT D816V mutation have improved our understanding of SM pathogenesis. […] The identification of early cooperating events for KIT mutations may improve our understanding of the pathogenesis of SM, leading to more efficient treatments and improved outcomes for SM patients. […] An increasing body of data has indicated that other events (e.g., tropomyosin-related kinase [TRK]) may play important roles in the pathogenesis of mastocytosis. […] Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Collectively, these data suggested that TRKA signaling may improve neoplastic MC fitness, which would explain, at least in part, why the results of treatment with KIT inhibitors alone in SM patients have been disappointing in most studies. […] The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies.

• #64 Rare diseases | Systemic Mastocytosis

  https://www.istitutogentili.com/en/rare-diseases/systemic-mastocytosis/

  Systemic mastocytosis (SM) is a rare disease resulting from the clonal expansion and accumulation of abnormal mast cells in various organs and tissues throughout the body. […] Mutations in the c-KIT gene activate the KIT receptor, even in the absence of its ligand. This mechanism: favours cell proliferation, reduces programmed cell death and, consequently, the accumulation of mast cells in certain organs and tissues of the human body. […] The treatment of systemic mastocytosis is tailored to the individual Patient based on: severity of the symptoms, manifestations of the disease, clinical evolution and prognosis. As there is no pharmacological treatment that is able to cure mastocytosis, the therapeutic options available have three aims: reduce the symptoms, by controlling the secretion and effects of mast cell mediators, reduce the extent of mast cell infiltration with cytoreduction therapies, treat the complications, such as organ dysfunction, caused by mast cell infiltration.

• #65 Management of Advanced Systemic Mastocytosis: Clinical Challenges | JBM

  https://www.dovepress.com/management-of-advanced-systemic-mastocytosis-clinical-challenges-peer-reviewed-fulltext-article-JBM

  It is now recognized that alternative activating mutations of KIT outside of D816V can also lead to MC activation, differentiation and proliferation and may alter the activation of the complex downstream signaling pathways. […] More than 90% of typical ISM and 70% of AdvSM carry acquired point mutation in the KIT gene. […] Additional somatic mutations (ASXL1, RUNX1, SRSF2, NRAS) have been found in 90% of ASM patients. […] The frequency of these mutations is significantly greater in AdvSM as compared to non-AdvSM, 19 of 27 non-KIT mutations were found in patients with advanced SM. […] The development of TKIs has revolutionized treatment for AdvSM. […] The D816V KIT point mutation also confers resistance against several tyrosine kinase inhibitors including imatinib. […] Given the impressive activity of selective KIT inhibition in reducing and in many cases eliminating KITD816V mutational burden, the concept of measurable residual disease (MRD) may now be relevant to AdvSM patients.

• #66 Management of Advanced Systemic Mastocytosis: Clinical Challenges | JBM

  https://www.dovepress.com/management-of-advanced-systemic-mastocytosis-clinical-challenges-peer-reviewed-fulltext-article-JBM

  It is now recognized that alternative activating mutations of KIT outside of D816V can also lead to MC activation, differentiation and proliferation and may alter the activation of the complex downstream signaling pathways. […] More than 90% of typical ISM and 70% of AdvSM carry acquired point mutation in the KIT gene. […] Additional somatic mutations (ASXL1, RUNX1, SRSF2, NRAS) have been found in 90% of ASM patients. […] The frequency of these mutations is significantly greater in AdvSM as compared to non-AdvSM, 19 of 27 non-KIT mutations were found in patients with advanced SM. […] The development of TKIs has revolutionized treatment for AdvSM. […] The D816V KIT point mutation also confers resistance against several tyrosine kinase inhibitors including imatinib. […] Given the impressive activity of selective KIT inhibition in reducing and in many cases eliminating KITD816V mutational burden, the concept of measurable residual disease (MRD) may now be relevant to AdvSM patients.

• #67 Diagnosis and treatment of systemic mastocytosis in Brazil: Recommendations of a multidisciplinary expert panel | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-diagnosis-treatment-systemic-mastocytosis-in-articulo-S2531137922000803

  Recommendation: The D816V KIT mutations should be investigated in all patients with Systemic Mastocytosis. […] The treatment of SM should be individualized and varies from a watch-and-wait period to the symptom management, supportive measures and cytoreductive therapy for MC debulking in the setting of aggressive, advanced or treatment-refractory disease. […] The cytoreductive therapy is indicated for patients with advanced systemic mastocytosis and for patients with indolent or smouldering Systemic Mastocytosis, for whom symptom therapy fails. […] The imatinib, a competitive inhibitor of several tyrosine kinases, including the KIT, has been tested in SM patients, with disappointing results. […] The resistance to imatinib in patients with the KIT D816V mutation may result from a conformational change in the activation loop located at the entrance to the KIT enzymatic pocket. […] The advanced SM (comprising patients with ASM, SM-AHN and MCL) treatment with midostaurin has been shown to deliver good results in an open-label study with 116 patients, with a 60% overall response rate, but no difference in the response according to the disease subtype.

• #68 Diagnosis and treatment of systemic mastocytosis in Brazil: Recommendations of a multidisciplinary expert panel | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-diagnosis-treatment-systemic-mastocytosis-in-articulo-S2531137922000803

  Recommendation: The D816V KIT mutations should be investigated in all patients with Systemic Mastocytosis. […] The treatment of SM should be individualized and varies from a watch-and-wait period to the symptom management, supportive measures and cytoreductive therapy for MC debulking in the setting of aggressive, advanced or treatment-refractory disease. […] The cytoreductive therapy is indicated for patients with advanced systemic mastocytosis and for patients with indolent or smouldering Systemic Mastocytosis, for whom symptom therapy fails. […] The imatinib, a competitive inhibitor of several tyrosine kinases, including the KIT, has been tested in SM patients, with disappointing results. […] The resistance to imatinib in patients with the KIT D816V mutation may result from a conformational change in the activation loop located at the entrance to the KIT enzymatic pocket. […] The advanced SM (comprising patients with ASM, SM-AHN and MCL) treatment with midostaurin has been shown to deliver good results in an open-label study with 116 patients, with a 60% overall response rate, but no difference in the response according to the disease subtype.

• #69 Target Therapies for Systemic Mastocytosis: An Update

  https://www.mdpi.com/1424-8247/15/6/738

  The impact of clonal architecture on responsiveness to midostaurin was explored in a group of 38 AdvSM patients. This study confirmed the negative prognostic impact of additional molecular aberrations in SRSF2, ASLX1, or RUNX1. ORR was significantly different between S/A/R negative (75%) and S/A/R positive (39%), in the same way, the median OS was 27 months for S/A/R positive patients and not reached for S/A/R negative patients.

• #70 Indolent Systemic Mastocytosis – AB Science

  https://www.ab-science.com/pipeline/masitinib-overview/indolent-systemic-mastocytosis/

  Mastocytosis is a rare disease characterized by proliferation and accumulation of mast cells in various tissues, causing a wide variety of clinical symptoms. […] Masitinibs anti-mast cell properties appear particularly well-adapted to the treatment of indolent systemic mastocytosis. A reduction of mast cell activity is generated via its inhibitory action on wild-type c-Kit, Lyn and Fyn tyrosine kinases. […] Masitinib also demonstrated significant activity on objective markers of mast cell activation and burden (i.e. level of tryptase, body surface area with urticaria pigmentosa, and presence of Dariers sign).

• #71 Current and Emergent Therapies for Systemic Mastocytosis

  https://www.targetedonc.com/view/current-and-emergent-therapies-for-systemic-mastocytosis

  Systemic mastocytosis (SM) is a hematologic neoplasm characterized by clonal proliferation of mast cells in 1 or more organs including skin, bone marrow, gastrointestinal tract, spleen and/or liver. The underlying molecular pathogenesis of SM is an activating mutation in the KIT gene that leads to the constitutive proliferation of mast cells. In nearly 95% of patients, this is the KIT D816V mutation in exon 17; most other cases also demonstrate other mutations (including in other exons) of KIT. […] The arrival of potent C-KIT inhibitors has ushered in a new area in the management of SM. Patients with advanced SM now have a targeted therapy available that provides more frequent and deeper remissions. Ongoing studies evaluating next generation C-KIT inhibitors will help address if a combinatorial or sequential approach with other therapies such as hypomethylating agents would help even more in preventing progression and inducing remissions while maintaining safety. The role of transplant in the era of potent C-KIT inhibitor therapy needs to be reanalyzed and assessed. On the other hand, for those with nonadvanced SM, the approval of avapritinib is a major win that improves symptoms and quality of life and possibly modifies the underlying disease biology. It will be important to demonstrate its long-term safety and tolerability in patients with ISM, and newer options for those who do not respond or lose response will be much welcome.

• #72 Current and Emergent Therapies for Systemic Mastocytosis

  https://www.targetedonc.com/view/current-and-emergent-therapies-for-systemic-mastocytosis

  Systemic mastocytosis (SM) is a hematologic neoplasm characterized by clonal proliferation of mast cells in 1 or more organs including skin, bone marrow, gastrointestinal tract, spleen and/or liver. The underlying molecular pathogenesis of SM is an activating mutation in the KIT gene that leads to the constitutive proliferation of mast cells. In nearly 95% of patients, this is the KIT D816V mutation in exon 17; most other cases also demonstrate other mutations (including in other exons) of KIT. […] The arrival of potent C-KIT inhibitors has ushered in a new area in the management of SM. Patients with advanced SM now have a targeted therapy available that provides more frequent and deeper remissions. Ongoing studies evaluating next generation C-KIT inhibitors will help address if a combinatorial or sequential approach with other therapies such as hypomethylating agents would help even more in preventing progression and inducing remissions while maintaining safety. The role of transplant in the era of potent C-KIT inhibitor therapy needs to be reanalyzed and assessed. On the other hand, for those with nonadvanced SM, the approval of avapritinib is a major win that improves symptoms and quality of life and possibly modifies the underlying disease biology. It will be important to demonstrate its long-term safety and tolerability in patients with ISM, and newer options for those who do not respond or lose response will be much welcome.

Zobacz więcej