Materiały źródłowe

• #1 Hairy Cell Leukemia – Leukemia – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK586203/

  The pathogenesis of HCL is not fully understood. Exposure to ionizing radiation, pesticides, and farming have been suggested as possible etiologies (810), cases of HCL have been reported among family members with the same HLA haplotype (11). In most patients, HCL arises from a late, activated memory B cell that acquires a single somatic point mutation in the DNA sequence of v-Raf murine sarcoma viral oncogene homolog B (BRAF), a kinase-encoding proto-oncogene (BRAFV600E) (12). […] The BRAFV600E mutation is detected in up to 8090% of classic HCL patients (13, 14). The mutation involves a thymine-to-adenine transversion at nucleotide in exon 15 of BRAF at position 1799 of the gene-coding sequence located in chromosome 7q34. The replacement produces an amino acid change from valine (V) to glutamate (E) at position 600 (V600E) of the protein sequence, ultimately leading to aberrant activation of BRAF kinase and the downstream MEK-ERK signaling. Indeed, the BRAFV600E mutation has been found to be more or less ubiquitous in studies involving hundreds of classic HCL patients (4, 15, 16).

• #1 Hairy Cell Leukemia | Cancer Genetics Web

  https://www.cancer-genetics.org/X1209.htm

  BRAFV600E mutation has been reported as a unique genetic lesion of hairy cell leukemia (HCL), a subset of which lacks this lesion and shows adverse outcomes. […] Recent studies revealed that the BRAF V600E mutation is the causal genetic event in HCL. […] The enigmatic pathogenesis of HCL was recently clarified by the discovery of its underlying genetic cause, the BRAF-V600E kinase-activating mutation, which is somatically and clonally present in almost all patients through the entire disease spectrum and clinical course. By aberrantly activating the RAF-MEK-ERK signaling pathway, BRAF-V600E shapes key biologic features of HCL, including its specific expression signature, hairy morphology, and antiapoptotic behavior. […] Accompanying mutations of the KLF2 transcription factor or the CDKN1B/p27 cell cycle inhibitor are recurrent in 16% of patients with HCL and likely cooperate with BRAF-V600E in HCL pathogenesis.

• #1 Hairy Cell Leukemia Pathogenesis, Diagnosis, and Prognosis

  https://www.onclive.com/view/hairy-cell-leukemia-pathogenesis-diagnosis-prognosis

  The pathogenesis, diagnostic criteria, staging, and prognosis of hairy cell leukemia, an uncommon indolent B-cell lymphoid neoplasm, is examined. […] The cellular origin of HCL has long been debated. […] The discovery of rearrangement of the B-cell receptor immunoglobulin genes in patients with the disease demonstrated that HCL has a B-cell origin. […] Studies conducted with monoclonal antibodies have confirmed that hairy cells are mature B cells. […] The discovery of these cell-surface markers led to the recognition of mature B cells as the origin of hairy cells. […] The BRAF V600E mutation is a causal genetic event in the development of HCL. […] Accumulating data suggest that the presence of BRAF V600E is the disease-causing event in HCL. […] This mutation is found in almost all cases of HCL, both at initial diagnosis and at relapse, regardless of the clinical presentation of the disease.

• #1 Hairy Cell Leukemia Pathogenesis, Diagnosis, and Prognosis

  https://www.onclive.com/view/hairy-cell-leukemia-pathogenesis-diagnosis-prognosis

  In vitro data suggest that silencing the RAF-MAPK/ERK kinase (MEK) pathway using BRAF or MEK inhibitors leads to loss of the HCL-specific gene expression profile signature, reverses the morphology of the cells from hairy to smooth, and induces apoptosis. […] Hairy cells express the activated integrin receptors 41 and V3 on their cell surface. […] The tissue infiltration process by hairy cells leads to bone marrow infiltration and hypersplenism, which contribute to the severe cytopenia reported in patients with HCL.

• #1 Evolving concepts in the pathogenesis of hairy-cell leukaemia | Nature Reviews Cancer

  https://www.nature.com/articles/nrc1888

  Hairy-cell leukaemia (HCL) is an indolent mature B-cell tumour of unknown genetic pathogenesis. Neoplastic cells have hair-like surface projections, infiltrate the bone marrow, the spleen and the liver, and circulate in low numbers in peripheral blood. […] The normal B-cell counterpart of HCL is still debated. However, its genome-wide expression signature and its mutated immunoglobulin genes suggest that HCL is derived from memory B cells, possibly from the splenic marginal zone (SMZ). […] Clonal expansion is largely the result of increased cell survival rather than proliferation. The growth properties of HCL are regulated by intracellular signalling pathways (including mitogen activated protein kinase (MAPK) cascades) and autocrine loops (including tumour necrosis factor- (TNF)TNF receptors (TNFRs)), with the microenvironment providing important pro-survival signals.

• #1 Hairy-Cell Leukemia — Onkopedia

  https://www.onkopedia.com/en/onkopedia/guidelines/hairy-cell-leukemia

  HCL is a malignant disease of B lymphocytes and is one of the indolent lymphomas. The cellular origin and early pathogenesis of HCL are unclear. It is certain that HCL originates from mature B cells. However, morphologically and phenotypically, HCL cells differ markedly from all previously known B cell populations. The clustered expression of somatically mutated immunoglobulin gene rearrangements and class-switched immunoglobulin isotypes in HCL are indicative of maturation of the cells of origin in germinal center reactions before or during early pathogenesis. A distinctive feature of HCL among all other B-cell malignancies is the simultaneous expression of multiple clonally related isotypes in approximately 40% of cases, sometimes even in single tumor cells. Reciprocal chromosomal translocations are absent. This is strong evidence that the cell of origin of HCL develops only after completion of a germinal center reaction. This assumption is supported by comparative analyses of transcriptome and epigenetic profiles of HCL and normal germinal center-experienced memory B cells, which show high similarity to each other.

• #1 The Biology of Classic Hairy Cell Leukemia

  https://www.mdpi.com/1422-0067/22/15/7780

  Finally, in 2011, Tiacci et al. identified a gain-of-function mutation of the B-rapidly accelerated fibrosarcoma (BRAF) serine/threonine protein kinase (V600E) detectably in almost all HCL patients. The activating BRAF mutation is a central genetic driver in HCL cells, as it is detected in the entire tumor clone and is highly stable at relapse. […] Taken together, these results suggest that cooperating genetic and/or epigenetic events are required to facilitate malignant transformation in BRAF V600E mutated HCL cells. […] The need for further ERK signaling modulation in BRAF-driven tumors indicates that a certain balance between ERK activation and inhibition is more important than the absolute ERK signaling strength for malignant transformation. […] Hence, downregulation of JNK/p38 signaling as a result of miRNA overexpression may represent another important mechanism helping HCL cells evade apoptosis.

• #1 Hairy Cell Leukemia: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/200580-overview

  Hairy cell leukemia is recognized as a clonal B-cell malignancy, as identified by immunoglobulin gene rearrangements that result in a phenotype B-cell expression of surface antigens. These reflect the differentiation between the immature B-cell of chronic lymphocytic leukemia and the plasma cell of multiple myeloma. […] The pathogenesis of HCL was clarified by the discovery of its underlying genetic cause, the BRAF V600E kinase-activating mutation, which is somatically and clonally present in almost all patients through the entire disease spectrum and clinical course. […] By aberrantly activating the RAF-MEK-ERK signaling pathway, BRAF V600E shapes key biologic features of HCL, including its specific expression signature, hairy morphology, and antiapoptotic behavior. […] Accompanying mutations of the KLF2 transcription factor or the CDKN1B/p27 cell cycle inhibitor are recurrent in 16% of patients with HCL and likely cooperate with BRAF V600E in HCL pathogenesis.

• #1 Hairy-Cell Leukemia — Onkopedia

  https://www.onkopedia.com/en/onkopedia/guidelines/hairy-cell-leukemia

  BRAF wild type is present in 5% of patients with classic HCL. Molecularly, this subgroup is associated with the IGHV 4-34 genotype and an unmutated IGHV status, clinically with a more aggressive course and poorer response to therapy with purine analogs. […] The HCL variant is biologically distinct. These leukemia cells have a BRAF wild type. They are commonly found to have the immunoglobulin heavy chain gene rearrangement IGHV4-34 and other genetic aberrations such as MAP2K, KMT2C or TP53 mutations.

• #1 Hairy Cell Leukemia: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/200580-overview

  Overexpression of cyclin D1 protein, an important cell-cycle regulator, has been observed in HCL and may play a role in the molecular pathogenesis of the disease. […] Accumulation of hairy cells in the bone marrow, liver, and spleen, with very little lymph node involvement, is characteristic of HCL. This pattern probably results from the expression of the integrin receptor alpha4-beta1 by the hairy cells and the interaction of the receptor with the vascular adhesion molecule-1 (VCAM-1) found in splenic and hepatic endothelia, bone marrow, and splenic stroma.

• #1 Hairy Cell Leukemia | Oncohema Key

  https://oncohemakey.com/hairy-cell-leukemia-4/

  It has been shown that CSF1R, which encodes the receptor for macrophage colony-stimulating factor and is normally expressed in macrophages/monocytes, is highly expressed in hairy cells. The addition of macrophage colony-stimulating factor to hairy cells causes enhanced mobility of the cells, the extent of which depends on the underlying stratum, and this effect is mediated through alterations in the integrin v4. […] The proposed effects of these changes on the pathophysiology of HCL are outlined in Table 91.1. […] Identified factors that may be involved include interleukin-2 (IL-2), tumor necrosis factor (TNF)-, IL-4, IL-6, B-cell growth factor, IFN-, transforming growth factor- (TGF-), and basic fibroblast growth factor (bFGF, FGF2). Some of these factors may be produced by the hairy cells themselves or by normal T-cells.

• #1 Hairy-Cell Leukemia — Onkopedia

  https://www.onkopedia.com/en/onkopedia/guidelines/hairy-cell-leukemia

  Moreover, HCL cells exhibit a similar pattern of cytokines, cytokine receptors, and adhesion molecules as activated splenic marginal zone B cells. This explains the unique dissemination of HCL cells and their interaction with accessory cells and the matrix proteins of the bone marrow stroma. […] Pathophysiologically, classic HCL and variants are distinct. Classic HCL is characterized by variable immunoglobulin heavy chain gene rearrangements (IGHV), activation of specific signal transduction pathways and the BRAF V600E mutation. The latter is detectable in almost all patients with classic HCL. Rarely, other mutations in the BRAF gene are detected. BRAF mutation leads to activation of the RAS-RAF-MAPK signal transduction pathway. BRAF-mutated stem cells from HCL patients can induce HCL-like disease in immunodeficient mice. Nevertheless, BRAF mutation alone is not sufficient for complete neoplastic HCL transformation, suggesting further genetic and/or epigenetic alterations. The second most common genetic aberrations in HCL are inactivating mutations of CDKN1B (approximately 16%). Furthermore, epigenetic machinery genes such as KMT2C, ARID1A/ARID1B, EZH2, and KDM6A are more frequently mutated. However, the functional context with BRAF V600E remains unclear.

• #1 Evolving concepts in the pathogenesis of hairy-cell leukaemia | Nature Reviews Cancer

  https://www.nature.com/articles/nrc1888

  Another unusual feature of HCL is bone-marrow fibrosis. Tumour cells secrete the fibrogenic cytokines basic fibroblast growth factor (bFGF) and tumour growth factor 1 (TGF1), which trigger the production of a fibronectin matrix by leukaemic cells and type III collagen fibres by fibroblasts, respectively. […] HCL-like disorders (HCL-variant (HCLv) and splenic lymphoma with villous lymphocytes (SLVL)) also present with splenomegaly, circulating 'hairy’ cells and infrequent lymph node involvement, but do not respond to IFN and purine analogues. […] In the future, elucidation of the key genetic lesions and molecular factors responsible for HCL development should lead to new, specific and less immunnosuppressive drugs. […] Gene-expression profiling and other studies have recently provided new insights into HCL biology and have the potential to affect clinical practice.

• #1 Hairy Cell Leukemia (HCL): Causes, Symptoms & Diagnosis

  https://myhematology.com/white-blood-cells/hairy-cell-leukemia/

  Hairy cells infiltrate the bone marrow, displacing normal hematopoietic cells. This infiltration leads to: Bone marrow fibrosis: The excessive accumulation of hairy cells can lead to fibrosis (scarring) of the bone marrow, further impairing its function. […] These factors collectively result in pancytopenia, a condition characterized by a decrease in all types of blood cells.

• #1 Hairy Cell Leukemia | Oncohema Key

  https://oncohemakey.com/hairy-cell-leukemia-4/

  It has been demonstrated that TNF-, but not TNF-, stimulates the growth of hairy cells, whereas in CLL, both forms of TNF stimulate leukemic cell growth. Hairy cells can also produce TNF-, and the serum level of TNF- is increased in HCL, the level correlating with tumor burden. […] The secreted bFGF then feeds back on the hairy cell to secrete fibronectin, which is a major component of the marrow fibrosis in this disease. As the spleen does not have hyaluronic acid, this explains the lack of bFGF and fibrosis in this organ despite abundant hairy cells.

• #1 The Biology of Classic Hairy Cell Leukemia

  https://www.mdpi.com/1422-0067/22/15/7780

  Nourishing crosstalk with specialized local stroma cells is vital for aggregation and persistence of HCL cells and responsible for the disease’s distinctive pattern of tissue infiltration. […] The relevance of BCR signaling in HCL is less well defined, although clear hints on a leading role in HCL biology date back to immunoglobulin analyses more than 10 years ago: Detection of mutated IGHV genes in nearly 90% of patients and restricted repertoire of IGHV gene usage, including IGHV3-21, IGHV3-30 and IGHV3-33, suggest some sort of selection pressure and indicate that BCR binding to similar, yet unknown, antigens may favor HCL transformation. […] The introduction of DNA and RNA single-cell sequencing studies of HCL cells and their local microenvironment may provide valuable insights to define the malignant cells’ clonal composition and better dissect the pathways involved in the crosstalk of HCL and their resource-rich surroundings. Ultimately, these studies may also help to identify the additional biologic features driving HCL besides the recurrent BRAF V600E mutation.

• #1 Hairy cell leukemia, an uncommon B-cell lymphoid neoplasia | Medicina Universitaria

  https://www.elsevier.es/en-revista-medicina-universitaria-304-articulo-hairy-cell-leukemia-an-uncommon-S1665579616300151

  HCL’s characteristic look is due to the beta-actin expression, which is polymerized to F-actin, located in the cortical cytoskeleton. […] On the other hand, HCL gene sequencing recently identified the presence of a BRAF V600E mutation in almost every patient with the disease, absent in other B-cell lymphoid malignancies. […] BRAF mutations activate the MAPK pathway, promoting growth, survival and HCL cell differentiation.

• #1 Pathology Outlines – Hairy cell leukemia

  https://www.pathologyoutlines.com/topic/lymphomahcl.html

  Hairy cell leukemia (HCL) is a rare, indolent lymphoproliferative neoplasm of mature B cells with a distinct clinical presentation that includes peripheral blood cytopenias, splenomegaly and a small number of circulating neoplastic cells with hair-like cytoplasmic projections. […] BRAF V600E mutation is the causal genetic event in the vast majority of HCL. Mutation constitutively activates BRAF by autophosphorylation of the protein and downstream MEK-ERK signaling pathway, leading to increased expression of genes involved in survival and proliferation and promoting leukemic transformation. […] Epidemiologic data shows a multifactorial etiology that is influenced by ethnicity and geographical factors. Farming and exposure to pesticides, petroleum products, diesel and ionizing radiation are associated with an increased risk. […] BRAF V600E mutation is a hallmark for classical HCL; this mutation is not seen in HCL variant.

• #1 Hairy Cell Leukemia | Cancer Genetics Web

  https://www.cancer-genetics.org/X1209.htm

  Thus, testing for BRAF-V600E allows for a genetics-based differential diagnosis between HCL and HCL-like tumors, even noninvasively in routine blood samples. […] BRAF-V600E also represents a new therapeutic target. […] The BRAF V600E mutation is now recognized as the causal genetic event of HCL because it is somatic, present in the entire tumor clone, detectable in almost all cases at diagnosis (encompassing the whole disease spectrum), and stable at relapse. […] BRAF V600E leads to the constitutive activation of the RAF-MEK-extracellular signal-regulated kinase (ERK) signaling pathway which represents the key event in the molecular pathogenesis of HCL. […] KLF2 and CDNK1B (p27) mutations may cooperate with BRAF V600E in promoting leukemic transformation. […] In vitro preclinical studies on purified HCL cells proved that BRAF and MEK inhibitors can induce marked dephosphorylation of MEK/ERK, silencing of RAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression profile signature, change of morphology from „hairy” to „smooth,” and eventually apoptosis.

• #1 Hairy Cell Leukemia Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/leukemia/hp/hairy-cell-treatment-pdq

  Hairy cell leukemia is an indolent, low-grade, B-cell lymphoid malignancy. It is rare, with only 1,200 to 1,300 new cases annually in the United States. […] The BRAF V600E pathogenic variant is a hairy cell leukemia defining genetic feature that can aid in diagnosis. […] There is a variation of hairy cell leukemia (HCL-v) which accounts for 10% of cases. HCL-v is distinguished clinically by an elevated white blood cell count (1550 109/L) and aberrant markers, including variable (instead of bright) CD103 and the absence of CD23, CD25, CD12, and CD43. […] BRAF inhibitors such as vemurafenib, dabrafenib, or encorafenib are nonchemotherapeutic options that can be combined with rituximab or obinutuzumab. […] Most patients with hairy cell leukemia have BRAF pathogenic variants, but this should be verified by flow cytometry.

• #1 Hairy Cell Leukemia | Cancer Genetics Web

  https://www.cancer-genetics.org/X1209.htm

  The overall response rate of refractory/relapsed HCL patients to the BRAF inhibitor vemurafenib approached 100%, with 35% to 40% complete remissions (CRs). […] Hairy cell leukemia (HCL) shows unique clinicopathological and biological features. HCL responds well to purine analogs but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). […] The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL.

• #2 Hairy Cell Leukemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499845/

  Hairy cell leukemia (HCL) is a rare, chronic B-cell malignancy that involves the spleen, bone marrow, and peripheral blood. […] The etiology of hairy cell leukemia is not well elucidated. However, previous exposure to various chemicals may play a role in its development. Most cases are postulated to be derived from V600E BRAF gene mutation of late activated memory B cells. […] As a lymphoproliferative neoplasm, Hairy cell leukemia is a clonal disorder. The relatively recent discovery of the presence of the V600E BRAF mutation in the vast majority of cases of classic Hairy cell leukemia has suggested that the pathogenesis of this disorder lies in the RAS-RAF-MAPK signaling pathway. Constitutive activity of this pathway leads to increased cellular proliferation and survival, and, ultimately, malignancy. A recent study by Sascha Dietrich et al. also found CDKN1B inactivation in 16% of patients with classical HCL. It is the second most commonly mutated gene in HCL.

• #2 Hairy Cell Leukemia: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/200580-overview

  Hairy cell leukemia is recognized as a clonal B-cell malignancy, as identified by immunoglobulin gene rearrangements that result in a phenotype B-cell expression of surface antigens. These reflect the differentiation between the immature B-cell of chronic lymphocytic leukemia and the plasma cell of multiple myeloma. […] The pathogenesis of HCL was clarified by the discovery of its underlying genetic cause, the BRAF V600E kinase-activating mutation, which is somatically and clonally present in almost all patients through the entire disease spectrum and clinical course. […] By aberrantly activating the RAF-MEK-ERK signaling pathway, BRAF V600E shapes key biologic features of HCL, including its specific expression signature, hairy morphology, and antiapoptotic behavior. […] Accompanying mutations of the KLF2 transcription factor or the CDKN1B/p27 cell cycle inhibitor are recurrent in 16% of patients with HCL and likely cooperate with BRAF V600E in HCL pathogenesis.

• #2 Hairy Cell Leukemia | Cancer Genetics Web

  https://www.cancer-genetics.org/X1209.htm

  Thus, testing for BRAF-V600E allows for a genetics-based differential diagnosis between HCL and HCL-like tumors, even noninvasively in routine blood samples. […] BRAF-V600E also represents a new therapeutic target. […] The BRAF V600E mutation is now recognized as the causal genetic event of HCL because it is somatic, present in the entire tumor clone, detectable in almost all cases at diagnosis (encompassing the whole disease spectrum), and stable at relapse. […] BRAF V600E leads to the constitutive activation of the RAF-MEK-extracellular signal-regulated kinase (ERK) signaling pathway which represents the key event in the molecular pathogenesis of HCL. […] KLF2 and CDNK1B (p27) mutations may cooperate with BRAF V600E in promoting leukemic transformation. […] In vitro preclinical studies on purified HCL cells proved that BRAF and MEK inhibitors can induce marked dephosphorylation of MEK/ERK, silencing of RAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression profile signature, change of morphology from „hairy” to „smooth,” and eventually apoptosis.

• #2 Rare Clinical Symptoms in Hairy Cell Leukemia: An Overview

  https://www.mdpi.com/2072-6694/16/17/3054

  The BRAF V600E mutation is present in almost all HCL patients and plays a key role in the pathogenesis of this disease. […] Extramedullary and extranodal manifestations of classic HCL are rare events. However, leukemic involvement in the skin, bone, central nervous system, gastrointestinal tract, heart, kidney, liver, lung, ocular system and other organs have been reported. […] Diagnosis is based on peripheral blood (PB) and bone marrow (BM) morphology, flow cytometry, immunophenotyping, immunohistochemistry and molecular studies. […] The characteristic immunophenotype of classic HCL cells includes the co-expression of CD19, CD20, CD11c, CD25, CD103, CD200, FMC7 and CD123. […] HCL variant (HCLv) is a clinical–pathologic entity with intermediate features between classic HCL and B-cell prolymphocytic leukemia.

• #2 The Biology of Classic Hairy Cell Leukemia

  https://www.mdpi.com/1422-0067/22/15/7780

  Finally, in 2011, Tiacci et al. identified a gain-of-function mutation of the B-rapidly accelerated fibrosarcoma (BRAF) serine/threonine protein kinase (V600E) detectably in almost all HCL patients. The activating BRAF mutation is a central genetic driver in HCL cells, as it is detected in the entire tumor clone and is highly stable at relapse. […] Taken together, these results suggest that cooperating genetic and/or epigenetic events are required to facilitate malignant transformation in BRAF V600E mutated HCL cells. […] The need for further ERK signaling modulation in BRAF-driven tumors indicates that a certain balance between ERK activation and inhibition is more important than the absolute ERK signaling strength for malignant transformation. […] Hence, downregulation of JNK/p38 signaling as a result of miRNA overexpression may represent another important mechanism helping HCL cells evade apoptosis.

• #2 Hairy cell leukemia, an uncommon B-cell lymphoid neoplasia | Medicina Universitaria

  https://www.elsevier.es/en-revista-medicina-universitaria-304-articulo-hairy-cell-leukemia-an-uncommon-S1665579616300151

  Hairy cell leukemia (HCL) is an uncommon B-cell lymphoid neoplasia, representing 23% of all leukemias. […] Although its etiology has not been established, the recent gene sequencing of HCL identified the presence of the BRAF V600E mutation, absent in other malignant neoplasias of the lymph cells. […] New discoveries in the pathophysiology of HCL have brought the creation of pharmaceuticals with distinct therapeutic targets. These pharmaceuticals are currently undergoing testing. […] HCL is a chronic, lymphoproliferative B-cell disorder. However, its cells do not have the appearance of any B-cell sub-population, and its origin has been a matter of debate. […] The analysis of immunoglobulins (Ig) variable regions genes is a tool used to discover the lymphoid cells clonal origin. […] Evidence suggests an origin post germinal center in memory B-cells, due to their genomic expression profile.

• #2 Hairy-Cell Leukemia — Onkopedia

  https://www.onkopedia.com/en/onkopedia/guidelines/hairy-cell-leukemia

  Moreover, HCL cells exhibit a similar pattern of cytokines, cytokine receptors, and adhesion molecules as activated splenic marginal zone B cells. This explains the unique dissemination of HCL cells and their interaction with accessory cells and the matrix proteins of the bone marrow stroma. […] Pathophysiologically, classic HCL and variants are distinct. Classic HCL is characterized by variable immunoglobulin heavy chain gene rearrangements (IGHV), activation of specific signal transduction pathways and the BRAF V600E mutation. The latter is detectable in almost all patients with classic HCL. Rarely, other mutations in the BRAF gene are detected. BRAF mutation leads to activation of the RAS-RAF-MAPK signal transduction pathway. BRAF-mutated stem cells from HCL patients can induce HCL-like disease in immunodeficient mice. Nevertheless, BRAF mutation alone is not sufficient for complete neoplastic HCL transformation, suggesting further genetic and/or epigenetic alterations. The second most common genetic aberrations in HCL are inactivating mutations of CDKN1B (approximately 16%). Furthermore, epigenetic machinery genes such as KMT2C, ARID1A/ARID1B, EZH2, and KDM6A are more frequently mutated. However, the functional context with BRAF V600E remains unclear.

• #2 Hairy Cell Leukemia | Cancer Genetics Web

  https://www.cancer-genetics.org/X1209.htm

  BRAFV600E mutation has been reported as a unique genetic lesion of hairy cell leukemia (HCL), a subset of which lacks this lesion and shows adverse outcomes. […] Recent studies revealed that the BRAF V600E mutation is the causal genetic event in HCL. […] The enigmatic pathogenesis of HCL was recently clarified by the discovery of its underlying genetic cause, the BRAF-V600E kinase-activating mutation, which is somatically and clonally present in almost all patients through the entire disease spectrum and clinical course. By aberrantly activating the RAF-MEK-ERK signaling pathway, BRAF-V600E shapes key biologic features of HCL, including its specific expression signature, hairy morphology, and antiapoptotic behavior. […] Accompanying mutations of the KLF2 transcription factor or the CDKN1B/p27 cell cycle inhibitor are recurrent in 16% of patients with HCL and likely cooperate with BRAF-V600E in HCL pathogenesis.

• #2 Hairy Cell Leukemia | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/22488

  As a lymphoproliferative neoplasm, Hairy cell leukemia is a clonal disorder. […] The relatively recent discovery of the presence of the V600E BRAF mutation in the vast majority of cases of classic Hairy cell leukemia has suggested that the pathogenesis of this disorder lies in the RAS-RAF-MAPK signaling pathway. […] Constitutive activity of this pathway leads to increased cellular proliferation and survival, and, ultimately, malignancy. […] A recent study by Sascha Dietrich et al. also found CDKN1B inactivation in 16% of patients with classical HCL. It is the second most commonly mutated gene in HCL.

• #2 Update on Hairy Cell Leukemia – Hematology & Oncology

  https://www.hematologyandoncology.net/archives/march-2018/update-on-hairy-cell-leukemia/

  Some patients with classic HCL have wild-type BRAF, as do essentially all patients with HCLv and/or IGHV4-34 immunoglobulin rearrangement. Up to 50% of these patients have mutations in MAP2K1 encoding mitogen-activated protein kinase enzyme 1 (MEK1), including mutations in U2AF1, ARID1A, TP53, TTN, KMT2C (previously MLL3), and CCND3.

• #2 Evolving concepts in the pathogenesis of hairy-cell leukaemia | Nature Reviews Cancer

  https://www.nature.com/articles/nrc1888

  Hairy-cell leukaemia (HCL) is an indolent mature B-cell tumour of unknown genetic pathogenesis. Neoplastic cells have hair-like surface projections, infiltrate the bone marrow, the spleen and the liver, and circulate in low numbers in peripheral blood. […] The normal B-cell counterpart of HCL is still debated. However, its genome-wide expression signature and its mutated immunoglobulin genes suggest that HCL is derived from memory B cells, possibly from the splenic marginal zone (SMZ). […] Clonal expansion is largely the result of increased cell survival rather than proliferation. The growth properties of HCL are regulated by intracellular signalling pathways (including mitogen activated protein kinase (MAPK) cascades) and autocrine loops (including tumour necrosis factor- (TNF)TNF receptors (TNFRs)), with the microenvironment providing important pro-survival signals.

• #2 Hairy Cell Leukemia Pathogenesis, Diagnosis, and Prognosis

  https://www.onclive.com/view/hairy-cell-leukemia-pathogenesis-diagnosis-prognosis

  In vitro data suggest that silencing the RAF-MAPK/ERK kinase (MEK) pathway using BRAF or MEK inhibitors leads to loss of the HCL-specific gene expression profile signature, reverses the morphology of the cells from hairy to smooth, and induces apoptosis. […] Hairy cells express the activated integrin receptors 41 and V3 on their cell surface. […] The tissue infiltration process by hairy cells leads to bone marrow infiltration and hypersplenism, which contribute to the severe cytopenia reported in patients with HCL.

• #2 Evolving concepts in the pathogenesis of hairy-cell leukaemia | Nature Reviews Cancer

  https://www.nature.com/articles/nrc1888

  The bone marrow fibrosis of hairy-cell leukemia is caused by the synthesis and assembly of a fibronectin matrix by the hairy cells. […] The role of autocrine FGF-2 in the distinctive bone marrow fibrosis of hairy-cell leukaemia (HCL). […] References 126, 128, 129 and 133 elucidate the molecular pathogenesis of bone-marrow fibrosis in HCL. […] Elucidates the important role of CDC42 and RAC1 in the 'hairy’ phenotype of leukaemic cells.

• #2 Hairy Cell Leukemia | Oncohema Key

  https://oncohemakey.com/hairy-cell-leukemia-4/

  It has been demonstrated that TNF-, but not TNF-, stimulates the growth of hairy cells, whereas in CLL, both forms of TNF stimulate leukemic cell growth. Hairy cells can also produce TNF-, and the serum level of TNF- is increased in HCL, the level correlating with tumor burden. […] The secreted bFGF then feeds back on the hairy cell to secrete fibronectin, which is a major component of the marrow fibrosis in this disease. As the spleen does not have hyaluronic acid, this explains the lack of bFGF and fibrosis in this organ despite abundant hairy cells.

• #2 Hairy cell leukemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Hairy_cell_leukemia_pathophysiology

  The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutation. […] The BRAF V600E mutation is present among most of the patients with hairy cell leukemia (classic). […] The BRAF V600E mutation is absent among patients with hairy cell leukemia (variant). […] The p38-MAPK-JNK cascade is inhibited, which will suppress the apoptotic signaling pathways. […] The MEK-ERK cascade is activated which will amplify the cytoprotective survival pathways. […] The phosphatidylinositol 3 kinase (PI3K)-AKT cascade is activated thus suppressing the apoptotic signaling pathways.

• #2 Hairy cell leukemia – Wikipedia

  https://en.wikipedia.org/wiki/Hairy_cell_leukemia

  Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. […] A 2011 study identified somatic BRAF V600E mutations in all 47 HCL patients studied, and no such mutations in the 193 peripheral B-cell lymphomas/leukemias other than HCL. […] Pancytopenia in HCL is caused primarily by marrow failure and splenomegaly. Bone-marrow failure is caused by the accumulation of hairy cells and reticulin fibrosis in the bone marrow, as well as by the detrimental effects of dysregulated cytokine production. […] Hairy cells are nearly mature B cells, which are activated clonal cells with signs of VH gene differentiation. […] Cytokine production is disturbed in HCL. Hairy cells produce and thrive on TNF-alpha. This cytokine also suppresses normal production of healthy blood cells in the bone marrow.

• #2 Clinical features and diagnosis of hairy cell leukemia – UpToDate

  https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-hairy-cell-leukemia/print

  Hairy cell leukemia (HCL) is an uncommon indolent lymphoid malignancy characterized by the accumulation of neoplastic B cells with abundant cytoplasm and „hairy” projections within the peripheral blood, bone marrow, and splenic red pulp. […] The pathogenesis of HCL is incompletely understood. Most cases are postulated to arise from a late, activated memory B cell that acquires a BRAF V600E gene mutation. The resultant aberrant activation of the RAF-MEK-ERK signaling pathway leads to a distinct phenotype and enhanced cell survival. […] Exposures to ionizing radiation, pesticides, and farming have been mentioned as possible causes. […] Cell of origin — HCL is postulated to arise from a late, activated memory B cell exhibiting preplasma cell or postgerminal center features.

• #2 Orphanet: Classic hairy cell leukemia

  https://www.orpha.net/en/disease/detail/58017

  A rare, slowly progressive, chronic leukemia characterized by presence of abnormal B-lymphocytes (medium sized with abundant irregular pale cytoplasm, hair-like cytoplasmic projections/ruffled cytoplasmic border, a round or bean-shaped nucleus and absent nucleoli) in the blood or bone marrow, spleen and peripheral blood pancytopenia, notable monocytopenia, and marked susceptibility to infection. The characteristic immunophenotype is CD11c+, CD25+, CD103+ and CD123+ with a BRAF mutation in most cases. […] Etiology is unknown. Family history of blood cancers, Ashkenazi Jewish heritage, occupational or environmental exposure to chemicals (e.g. insecticides) are considered as possible risk factors. BRAFV600E mutation, which causes constitutive activation of the MAP kinase pathway, is also found in most patients with HCLc. […] Characteristic immunophenotypic markers include CD11c, CD25, CD103, CD123 positive. BRAF-V600E mutation is also found in most patients.

• #2 Hairy Cell Leukemia | Cancer Genetics Web

  https://www.cancer-genetics.org/X1209.htm

  The overall response rate of refractory/relapsed HCL patients to the BRAF inhibitor vemurafenib approached 100%, with 35% to 40% complete remissions (CRs). […] Hairy cell leukemia (HCL) shows unique clinicopathological and biological features. HCL responds well to purine analogs but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). […] The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL.

• #2 Hairy Cell Leukemia Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/leukemia/hp/hairy-cell-treatment-pdq

  BRAF V600E pathogenic variants are found in almost 100% of patients with classic-form hairy cell leukemia and almost never found in patients with other B-cell lymphomas and leukemias, including HCL-v. […] The FDA has not approved BRAF inhibitors for hairy cell leukemia, but they can be used off-label in clinical practice.

• #3 The Biology of Classic Hairy Cell Leukemia

  https://www.mdpi.com/1422-0067/22/15/7780

  Finally, in 2011, Tiacci et al. identified a gain-of-function mutation of the B-rapidly accelerated fibrosarcoma (BRAF) serine/threonine protein kinase (V600E) detectably in almost all HCL patients. The activating BRAF mutation is a central genetic driver in HCL cells, as it is detected in the entire tumor clone and is highly stable at relapse. […] Taken together, these results suggest that cooperating genetic and/or epigenetic events are required to facilitate malignant transformation in BRAF V600E mutated HCL cells. […] The need for further ERK signaling modulation in BRAF-driven tumors indicates that a certain balance between ERK activation and inhibition is more important than the absolute ERK signaling strength for malignant transformation. […] Hence, downregulation of JNK/p38 signaling as a result of miRNA overexpression may represent another important mechanism helping HCL cells evade apoptosis.

• #3 Hairy-Cell Leukemia — Onkopedia

  https://www.onkopedia.com/en/onkopedia/guidelines/hairy-cell-leukemia

  HCL is a malignant disease of B lymphocytes and is one of the indolent lymphomas. The cellular origin and early pathogenesis of HCL are unclear. It is certain that HCL originates from mature B cells. However, morphologically and phenotypically, HCL cells differ markedly from all previously known B cell populations. The clustered expression of somatically mutated immunoglobulin gene rearrangements and class-switched immunoglobulin isotypes in HCL are indicative of maturation of the cells of origin in germinal center reactions before or during early pathogenesis. A distinctive feature of HCL among all other B-cell malignancies is the simultaneous expression of multiple clonally related isotypes in approximately 40% of cases, sometimes even in single tumor cells. Reciprocal chromosomal translocations are absent. This is strong evidence that the cell of origin of HCL develops only after completion of a germinal center reaction. This assumption is supported by comparative analyses of transcriptome and epigenetic profiles of HCL and normal germinal center-experienced memory B cells, which show high similarity to each other.

• #3 Hairy Cell Leukemia | Oncohema Key

  https://oncohemakey.com/hairy-cell-leukemia-4/

  Immunologic, molecular genetic, chromosomal, and gene expression studies have demonstrated that the hairy cell is of B-cell origin. Gene expression profiling has demonstrated that the hairy cell is most similar to a memory B-cell, although it differs in that the hairy cell has increased expression of adhesion and chemokine receptor genes. The profile is extremely homogeneous, quite different from other lymphoid malignancies, and the abnormal expression of specific genes explains the properties of this disease which include unique cell structure, marrow fibrosis, marrow suppression, and the tendency of tumor cells to home to spleen and marrow, rather than to lymph nodes. […] The majority of cases with HCL show mutations of the variable chain of the Ig gene, demonstrating that the hairy cell has passed through the germinal center. However, 10% to 20% of cases have unmutated IgVH and in general these patients have very poor prognosis and are resistant to chemotherapy.

• #3 Hairy-Cell Leukemia — Onkopedia

  https://www.onkopedia.com/en/onkopedia/guidelines/hairy-cell-leukemia

  Moreover, HCL cells exhibit a similar pattern of cytokines, cytokine receptors, and adhesion molecules as activated splenic marginal zone B cells. This explains the unique dissemination of HCL cells and their interaction with accessory cells and the matrix proteins of the bone marrow stroma. […] Pathophysiologically, classic HCL and variants are distinct. Classic HCL is characterized by variable immunoglobulin heavy chain gene rearrangements (IGHV), activation of specific signal transduction pathways and the BRAF V600E mutation. The latter is detectable in almost all patients with classic HCL. Rarely, other mutations in the BRAF gene are detected. BRAF mutation leads to activation of the RAS-RAF-MAPK signal transduction pathway. BRAF-mutated stem cells from HCL patients can induce HCL-like disease in immunodeficient mice. Nevertheless, BRAF mutation alone is not sufficient for complete neoplastic HCL transformation, suggesting further genetic and/or epigenetic alterations. The second most common genetic aberrations in HCL are inactivating mutations of CDKN1B (approximately 16%). Furthermore, epigenetic machinery genes such as KMT2C, ARID1A/ARID1B, EZH2, and KDM6A are more frequently mutated. However, the functional context with BRAF V600E remains unclear.

• #3

  https://link.springer.com/article/10.1007/s11912-023-01419-z

  Hairy cell leukemia (HCL) is a rare hematological malignancy that arises from late-activated post-germinal center memory B-cells. […] The BRAF V600E mutation, which is also seen in solid tumors such as melanoma and lung cancer, has since been shown to be present in the vast majority of cases of HCL and constitutes an activating mutation which translates into increased proliferation and survival of malignant cells. […] Patients with a classical immunophenotype but who lack BRAF V600E may harbor alternative BRAF mutations. […] Additional driver mutations in the MAP2K1 pathway may be present, and one case series demonstrated MAP2K1 mutations in one-third of those who were unmutated for BRAF. […] The mechanism of monocytopenia remains elusive. […] HCL has been associated with worse outcomes in patients with splenomegaly, higher beta-2 microglobulin, leukocytosis (10109/L), and an elevated hairy cell count (5109/L).

• #3 Hairy cell leukemia (Chapter 7) – Management of Hematologic Malignancies

  https://www.cambridge.org/core/books/management-of-hematologic-malignancies/hairy-cell-leukemia/E6C4592036823911BB563F26152CF566

  Hairy cell leukemia (HCL) is a rare, chronic lymphoproliferative disorder characterized by splenomegaly, pancytopenia, bone marrow fibrosis, and frequent infectious complications. Its hallmark is the hairy cell, a small- to medium-sized mononuclear cell with a typical serrated border and cytoplasmic projections. […] HCL has no known cause and risk factors are poorly characterized. Farming or woodworking, or occupational exposure to organic solvents, resulted in a higher relative risk for developing HCL. Infectious mononucleosis has been associated with HCL, but a pathogenic role for EpsteinBarr virus has been disputed. Studies evaluating radiation exposure as a HCL risk factor have also produced conflicting results. […] The bone marrow fibrosis of hairy-cell leukemia is caused by the synthesis and assembly of a fibronectin matrix by the hairy cells. […] Involvement of CD44-hyaluronan interaction in malignant cell homing and fibronectin synthesis in hairy cell leukemia.

• #3 Hairy cell leukemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Hairy_cell_leukemia_pathophysiology

  Hairy cell leukemia arises from B cells that are normally involved in the process of human immunoglobulins production. However, the exact B cell maturation stage involved in the development of hairy cell leukemia is still unclear. The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutation. […] Bone marrow failure may develop among hairy cell leukemia patients due to: […] The development of bone marrow failure interferes with the normal production of red blood cells and platelets among hairy cell leukemia patients. […] Production of cytokines, such as TNF alpha and IL-2, provide important stimuli for malignant B cells proliferation in hairy cell leukemia. […] Leukemic cells demonstrate prolonged survival due to the up-regulation of apoptosis-inhibitors such as IAP1 and IAP2 by TNF alpha.

• #3

  https://link.springer.com/article/10.1007/BF02685898

  Constitutively activated Rho guanosine triphosphatases regulate the growth and morphology of hairy cell leukemia cells. […] RhoGTPases and p53 are involved in the morphological appearance and interferonalpha response of hairy cells. […] The role of autocrine FGF-2 in the distinctive bone marrow fibrosis of hairy-cell leukemia (HCL).

• #3 Hairy Cell Leukemia | Oncohema Key

  https://oncohemakey.com/hairy-cell-leukemia-4/

  Hairy cell leukemia (HCL), or leukemic reticuloendotheliosis, is a chronic B-cell disorder that was initially described by Bouroncle et al. in 1958. The disease is characterized by the presence of typical hairy cells in the peripheral blood and marrow, pancytopenia, and a variable degree of splenomegaly. More recently, it has been demonstrated that most hairy cells contain a mutated active form of the BRAF gene (V600E) which may be used as a diagnostic tool and a potential target for therapy. […] The etiology of HCL is unknown. Several case-controlled studies have identified possible relationships to radiation exposure, exposure to benzene, to farm animals, and to commercial herbicides and pesticides. A familial predisposition is suggested by reports of the disorder in 15 families where HCL occurred among first-degree relatives.

• #3 HCL2025 — Hairy Cell Leukemia Foundation

  https://www.hairycellleukemia.org/hcl2025

  We hypothesize that their attenuation compromises HCL cell survival. […] Hairy cell leukemia (HCL) is very sensitive to chemotherapy, whose toxicity to the bone marrow and the immune system is however concerning. […] The investigators have established vemurafenib plus rituximab as a very effective chemotherapy-free regimen in relapsed/refractory HCL. […] We hypothesize BAFF CAR-T will be an effective therapeutic strategy for HCL. […] We will apply our innovative platforms of digital spatial profiling, whole genome sequencing and circulating tumor DNA to provide highly novel data from our already collected sample bank from over 60 patients with HCL. […] New molecularly-targeted therapies such as BRAF, MEK and BTK inhibitors provide non-chemotherapy options in HCL. […] The genomic mechanisms of resistance and the immune impact of these novel agents in HCL are largely unknown and may be of value for guiding subsequent therapy decisions. […] We expect to identify HCL specific and BRAF-dependent surfaceomes and identify new and critical targets for treatment.

• #3 Hairy Cell Leukemia | Cancer Genetics Web

  https://www.cancer-genetics.org/X1209.htm

  The overall response rate of refractory/relapsed HCL patients to the BRAF inhibitor vemurafenib approached 100%, with 35% to 40% complete remissions (CRs). […] Hairy cell leukemia (HCL) shows unique clinicopathological and biological features. HCL responds well to purine analogs but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). […] The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL.

• #4 Hairy Cell Leukemia – Leukemia – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK586203/

  The mutation is responsible for continuous BRAF activation, and, in turn, provides continuous signaling to the RASRAFMEK-ERK signaling pathway, whose aberrant activation activates a distinct phenotype and enhances the survival of the HCL cell. […] In addition to the BRAFV600E mutation, the most common genetic alteration in classical HCL is a loss in copy number for chromosome 7q (13). A mutated immunoglobulin heavy chain variable region (IGHV) gene profile is detected in 90% of HCL patients. The absence of a BRAF mutation (BRAFWT) is associated with the activation of mutations in the mitogen-activated protein kinase kinase 1 (MAP2K1) gene by unmutated IGHV and VH4-34 rearrangements (18); this small subset of classic HCL patients has poor prognosis and poor response to nucleoside purine analogs (PNAs). In addition, a whole-exome sequencing study of patients with classic HCL confirmed the presence of various cancer-associated genes, including EZH2 and ARID1A, together with novel inactivating mutations of the cell cycle inhibitor CDKN1B (p27) (19). CDKN1B is the second most commonly mutated gene in HCL.

• #4 Hairy cell leukemia: short review, today’s recommendations and outlook | Blood Cancer Journal

  https://www.nature.com/articles/bcj20143

  The BRAF V600E mutation seems to have an important role in the pathogenesis of HCL if it is not even the disease-defining genetic event. […] This mutation can be regarded as the key trigger of MEK-ERK pathway activation in HCL, representing a critical event in the pathogenesis of HCL. […] These new insights of the pathogenesis of HCL may also allow new therapeutic options, especially for patients who need an alternative to PA because of non-sufficient response, persistence of BRAF-V600E at partial remission, relapse or toxic side effects of chemotherapy.

• #4 The Biology of Classic Hairy Cell Leukemia

  https://www.mdpi.com/1422-0067/22/15/7780

  Nourishing crosstalk with specialized local stroma cells is vital for aggregation and persistence of HCL cells and responsible for the disease’s distinctive pattern of tissue infiltration. […] The relevance of BCR signaling in HCL is less well defined, although clear hints on a leading role in HCL biology date back to immunoglobulin analyses more than 10 years ago: Detection of mutated IGHV genes in nearly 90% of patients and restricted repertoire of IGHV gene usage, including IGHV3-21, IGHV3-30 and IGHV3-33, suggest some sort of selection pressure and indicate that BCR binding to similar, yet unknown, antigens may favor HCL transformation. […] The introduction of DNA and RNA single-cell sequencing studies of HCL cells and their local microenvironment may provide valuable insights to define the malignant cells’ clonal composition and better dissect the pathways involved in the crosstalk of HCL and their resource-rich surroundings. Ultimately, these studies may also help to identify the additional biologic features driving HCL besides the recurrent BRAF V600E mutation.

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