Materiały źródłowe

• #1 Molecular pathogenesis of Waldenström’s macroglobulinemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3436227/

  Waldenstrms macroglobulinemia is an indolent, lymphoproliferative disease, characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and high immunoglobulin M production. […] the pathogenesis of the disease remains fragmented. […] research has been successful in uncovering underlying aberrations and deregulated mechanisms in this disease, providing useful information for identifying biomarkers for disease diagnosis, risk stratification and therapeutic intervention, but there is still a long way to go before the pathogenesis of Waldenstrms macroglobulinemia is fully revealed. […] The existence of somatic hypermutation in WM indicates a role for antigenic stimulation in the development of WM. […] Environmental and inherited factors may contribute to familial IgM-MGUS/WM clusters.

• #2 Pathophysiology of Waldenström’s macroglobulinemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2833063/

  Waldenstrms macroglobulinemia (WM) is classified as an indolent form of B-cell non-Hodgkins lymphoma known in the World Health Organization (WHO) classification as lymphoplasmacytic lymphoma. Infiltration with clonal lymphoplasmacytic cells, predominantly in the bone marrow, and an IgM monoclonal gammopathy are diagnostic findings. The development of WM is preceded by an IgM monoclonal gammopathy of undetermined significance (MGUS) in most, perhaps all, patients. […] Genetic analysis of the VH regions from patients with WM and IgM MGUS indicate that both develop from a post-germinal center cell that has undergone somatic hypermutation, possibly under the influence of antigen selection, but not isotype switching. Thus, WM and IgM MGUS arise from an IgM-expressing cell that transforms after cessation of somatic mutation, but without initiating switch events.

• #3

  https://haematologica.org/article/view/6396

  Waldenstrms macroglobulinemia is an indolent, lymphoproliferative disease, characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and high immunoglobulin M production. […] the pathogenesis of the disease remains fragmented. Undoubtedly, research has been successful in uncovering underlying aberrations and deregulated mechanisms in this disease, providing useful information for identifying biomarkers for disease diagnosis, risk stratification and therapeutic intervention, but there is still a long way to go before the pathogenesis of Waldenstrms macroglobulinemia is fully revealed. […] The existence of somatic hypermutation in WM indicates a role for antigenic stimulation in the development of WM. […] Environmental and inherited factors may contribute to familial IgM-MGUS/WM clusters.

• #4 Waldenström’s macroglobulinemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Waldenstr%C3%B6m%27s_macroglobulinemia_pathophysiology

  Waldenstrom’s macroglobulinemia is an uncontrolled clonal proliferation of terminally differentiated B lymphocytes, which are normally involved in humoral immunity. […] Two main factors mediating this disease include IgM paraprotein secretion and tissue infiltration with neoplastic lymphoplasmacytic cells. […] Genes involved in the pathogenesis of WM include MYD88-L265P, and CXCR4 along with various other cytogenetic and epigenetic abnormalities. […] The exact pathogenesis of Waldenstrom’s macroglobulinemia is not completely understood; however, its familial pattern of involvement supports the role played by genetic factors in the pathogenesis of this disease. […] Development of WM is the result of multiple genetic mutations. […] A mutation of the MYD88 gene (L265P) has been found in more than 90% of patients with Waldenstrom’s macroglobulinemia, while it has rarely presented in patients with other types of mature B-cell tumors.

• #5 Waldenstrom Macroglobulinemia: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/207097-overview

  The clinical manifestations of this disorder result from 2 important factors. First, secretion of the IgM paraprotein leads to hyperviscosity and vascular complications because of physical, chemical, and immunologic properties of the paraprotein. These complications include the following: […] Second, neoplastic lymphoplasmacytic cells infiltrate the bone marrow, spleen, and lymph nodes. Less commonly, these cells can infiltrate the liver, lungs, GI tract, kidneys, skin, eyes, and central nervous system (CNS). Infiltration of these organs causes numerous clinical symptoms and signs. […] The MYD88 L265P somatic mutation, in which leucine is replaced by proline at position 265, is found in white blood cells in approximately 90% of Waldenstrm macroglobulinemia cases. The mutation results in overactivity of the altered MyD88 protein, stimulating the signaling molecules that activate nuclear factor-kappa-B; this may protect lymphoplasmacytic cells against apoptosis.

• #6

  https://haematologica.org/article/view/5519

  Waldenstrms macroglobulinemia (WM) is classified as an indolent form of B-cell non-Hodgkins lymphoma known in the World Health Organization (WHO) classification as lymphoplasmacytic lymphoma. Infiltration with clonal lymphoplasmacytic cells, predominantly in the bone marrow, and an IgM monoclonal gammopathy are diagnostic findings. The development of WM is preceded by an IgM monoclonal gammopathy of undetermined significance (MGUS) in most, perhaps all, patients. […] Genetic analysis of the VH regions from patients with WM and IgM MGUS indicate that both develop from a post-germinal center cell that has undergone somatic hypermutation, possibly under the influence of antigen selection, but not isotype switching. Thus, WM and IgM MGUS arise from an IgM-expressing cell that transforms after cessation of somatic mutation, but without initiating switch events.

• #7 Pathophysiology of Waldenström’s macroglobulinemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2833063/

  The WM cell could arise from a memory-like, somatically mutated precursor that has lost classic memory markers such as CD27 due to shedding from the surface. […] Shedding of CD27 from the WM cell could have pathogenic implications. This molecule activates surrounding mast cells in the bone marrow to produce B cell activators and survival factors such as CD40L and APRIL that could drive the lymphoplasmacytoid differentiation of the WM clone. […] Thus, WM could arise from a mature, memory-like B cell of either marginal zone or germinal center origin which does not undergo downstream switching but is able to acquire a lymphoplasmacytoid phenotype and IgM secretory capacity. Whether this lymphoplasmacytoid differentiation is due to intrinsic alterations related to the malignant transformation event or is secondary to extrinsic factors, such as the expression of tumor necrosis factor family members on neighboring bone marrow mast cells, remains to be elucidated. […] Gene expression profiling further supports the understanding that these cells are closer in their transcriptome make up to malignant mature B cells (i.e. chronic lymphocytic leukemia) than to plasma cells.

• #8 SciELO Brazil – Waldenström’s macroglobulinemia – a review Waldenström’s macroglobulinemia – a review

  https://www.scielo.br/j/ramb/a/sFTFrpnLqRXq8RfHvD7BpMk/

  In WM, malignant B-lymphocytes express the receptor CD27, which can be found in the membrane of memory B-lymphocytes and in soluble form (sCD27) in high concentrations in the serum. […] sCD27 activates bone marrow mast cells by binding to CD70. […] Activated mast cells secrete growth and survival factors for B-lymphocytes such as CD40L and APRIL (proliferation-inducing ligand), which may contribute to lymphoplasmocytoid differentiation of malignant cells in the bone marrow.

• #9

  https://haematologica.org/article/view/5519

  Gene expression profiling further supports the understanding that these cells are closer in their transcriptome make up to malignant mature B cells (i.e. chronic lymphocytic leukemia) than to plasma cells. When compared to healthy mature B cells and chronic lymphocytic leukemia cells, WM cells over-express interleukin-6, a cytokine that promotes plasma cell differentiation. […] A familial predisposition to WM has been documented by several groups. For example, a patient with Waldenstrms macroglobulinemia for 37 years had three children with IgM M-spikes and/or hypogammaglobulinemia. As many as 20% of WM patients have a family member with such immunoglobulin abnormalities. […] The basis for hypogammaglobulinemia in these individuals is not clear but it is possible that the lower levels of IgG and IgA pre-date the development of WM. Thus, familial dysregulation of immunoglobulin production could be an event upstream of the malignant transformation in a way reminiscent of the role that chronic antigenic stimulation plays in MALT lymphoma.

• #10 SciELO Brazil – Waldenström’s macroglobulinemia – a review Waldenström’s macroglobulinemia – a review

  https://www.scielo.br/j/ramb/a/sFTFrpnLqRXq8RfHvD7BpMk/

  In relation to the mechanisms involved in the pathophysiology of WM, the blocking of immunoglobulin isotype switching and the role of cytokines is noteworthy. […] Most malignant cells in WM express surface IgM and IgD, suggesting an intrinsic incapacity to switch isotypes. […] This „block” may be related to the absence/dysfunction of the activation-induced cytidine deaminase (AID) enzyme, which is involved in somatic hypermutation and the immunoglobulin isotype switching process. […] Although isotype switching is rarely seen in WM, according to some studies it is possible that it occurs ex vivo and in vivo. […] Mast cells and various cytokines play an important role in the development of the disease. […] Cytokines may be important for angiogenesis, increased bone resorption, proliferation, survival of malignant cells, and secretion of monoclonal IgM.

• #11 Waldenström macroglobulinemia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/waldenstrom-macroglobulinemia/

  Waldenström macroglobulinemia is a rare blood cell cancer characterized by an excess of abnormal white blood cells in the bone marrow. […] It is not clear what causes Waldenström macroglobulinemia, though it is likely to result from a combination of genetic changes. The most common known genetic change associated with this condition is a variant (also called mutation) in the MYD88 gene, which is found in more than 90 percent of affected individuals. […] The proteins produced from the MYD88 and CXCR4 genes are both involved in signaling within cells. The MyD88 protein relays signals that help prevent the self-destruction (apoptosis) of cells, thus aiding in cell survival. […] Variants in these genes lead to production of proteins that are constantly turned on (overactive). Excessive signaling through these overactive proteins allows survival and proliferation of abnormal cells that should undergo apoptosis, which likely contributes to the accumulation of lymphoplasmacytic cells in Waldenström macroglobulinemia.

• #12 Waldenström Macroglobulinemia – Hematology & Oncology

  https://www.hematologyandoncology.net/archives/january-2015/waldenstrom-macroglobulinemia/

  Somatic mutations in MYD88 L265P and the WHIM-like CXCR4 are common findings in patients with WM and have implications for the pathogenesis and outcome of patients with WM. […] MYD88 mutations are seen in more than 90% of patients with WM, and CXCR4 mutations are seen in up to 30% of patients. […] The particular type (frameshift, nonsense) and combination of the mutations seen in patients with WM impacts the clinical presentation and offers insights into prognosis and potential drug resistance.

• #13 Waldenström’s macroglobulinemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Waldenstr%C3%B6m%27s_macroglobulinemia_pathophysiology

  MYD88: The activating point mutation of MYD88 augments signaling by Toll-like receptor and Bruton tyrosine kinase (BTK), which leads to activation of transcription factors of the NF-kB family which are involved in growth and survival of both normal and neoplastic B cells by preventing apoptosis. […] Less commonly (30-35%), nonsense or frameshift mutations in the C-X-C chemokine receptor type 4 (CXCR4) 5338X gene have also been reported in patients with Waldenstrom’s macroglobulinemia. […] Patients with Waldenstrom’s macroglobulinemia with co-existing mutation of MYD88 CXCR4 are more likely to have hyper-viscosity syndrome and bone marrow involvement. […] Many cytogenetic abnormalities were reported in Waldenstrom’s macroglobulinemia’s patients including: Deletion of the long arm of chromosome 6q21-22.1 (most common, 50%).

• #14 Current Therapeutic Options in Waldenstrom Macroglobulinemia

  https://touchoncology.com/haematological-malignancies/journal-articles/current-therapeutic-options-in-waldenstrom-macroglobulinemia/

  Waldenstrm macroglobulinemia (WM) represents an indolent immunoglobulin M (IgM)-associated B-cell lymphoplasmacytic lymphoma with a myriad of presenting features. […] A highly recurrent, clonal point mutation in the MYD88 gene is detected in 80-95% of patients. Nonsense or frameshift somatic mutations in the CXCR4 gene occur in 30-40% of patients. These mutations may carry significance in terms of both the presenting symptoms and therapy selection. […] The most common somatic mutation in WM is a point mutation (L265P) in the gene coding for the myeloid differentiation primary response 88 (MYD88) protein associated with the B-cell receptor pathway and is encountered in 80-95% of WM cases. […] The mutation in the MYD88 gene leads to a constitutive homodimerization of the MYD88 adaptor protein, resulting in downstream signaling through Bruton tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1)/IRAK4 kinases and transactivation of hematopoietic cell kinase (HCK), ultimately leading to WM cell survival and proliferation through upregulation of the nuclear factor kappa beta (NFB) pathway.

• #15 Bing Center for Waldenstrom’s Macroglobulinemia – Genomics, Signaling and Treatment of Waldenström’s Macroglobulinemia

  https://www.waldenstroms.com/?view=article&id=417&catid=23

  Waldenström’s macroglobulinemia (WM) is a distinct B-cell malignancy that results from the accumulation, predominantly in the bone marrow, of clonally related B type lymphocytes, lymphoplasmacytic cells and plasma cells which secrete a monoclonal IgM protein. […] Genetic factors appear to be an important to the pathogenesis of WM. A common predisposition for WM with other malignancies has been raised, with numerous reports of familial clustering of individuals with WM alone, and with other B-cell derived malignancies. […] Several rare inherited gene variants as well as the over-expression of the BCL2 protein (a protein which blocks cell death) have been proposed as predisposition events, however further confirmation and characterization of these findings is needed. […] MYD88 mutations encompass the entire WM clone, and are detectable in 50-80% of IgM but not IgG or IgA MGUS suggesting an early oncogenic role for WM pathogenesis.

• #16

  https://juniperpublishers.com/oabtj/OABTJ.MS.ID.555603.php

  The main conclusion of the presented in the current research paper is that Wald Enstrom macroglobulinemia disease remains to be an incurable disease with heterogeneous clinical course and genetics enhanced our understanding of its pathogenesis. […] The presence of MYD88L265P in the precancerous IgM-MGUS suggests that this mutation represents an early oncogenic event in WM pathogenesis. […] Studies of signaling pathways demonstrated that the mutant protein encoded by the MYD88L265P triggers tumor growth through the activation of nuclear factor kappa lightchain enhancer of activated B cells (NF-B) by Brutons tyrosine kinase and IRAK1/IRAK4. […] MYD88 mutation has a prevalence in Waldenstrm macroglobulinemia of 87 to 100% and CXCR4 is the next most common.

• #17 Diagnostics in Waldenström’s macroglobulinemia: a consensus statement of the European Consortium for Waldenström’s Macroglobulinemia | Leukemia

  https://www.nature.com/articles/s41375-022-01762-3

  Important advances in understanding the biology of WM have been made in recent years, leading to an increased toolset for differential diagnosis. Using whole genome sequencing, Treon et al. identified MYD88L265P as a highly recurrent (~95%) somatic mutation in patients with WM. Several studies using different techniques, such as Sanger sequencing, and allele-specific quantitative PCR (ASqPCR), confirmed that MYD88L265P is present in 90% of WM, whereas it is absent in patients with multiple myeloma (MM) (including IgM isotype), and less frequently found in marginal zone lymphoma (MZL) with plasmacytic differentiation or chronic lymphocytic leukemia (CLL). Therefore, MYD88L265P assessment is considered crucial to discriminate between WM and other B-LPDs with overlapping clinical features. […] Mutations in the CXCR4 gene were identified as the second most common alterations in WM (30-40% patients) and play an important role in WM pathogenesis and disease progression. These mutations might also impact the clinical presentation and outcome of WM patients. Thus, MYD88L265P/CXCR4WHIM patients may present with a more aggressive clinical behavior, and inferior response to Bruton Tyrosine Kinase inhibitors (BTKi). On the other hand, higher risk of transformation to aggressive lymphoma and shorter overall survival were reported in MYD88 wild-type cases.

• #18 Waldenstrom macroglobulinemia: biology, genetics, and therapy | BLCTT

  https://www.dovepress.com/waldenstroumlm-macroglobulinemia-biology-genetics-and-therapy-peer-reviewed-fulltext-article-BLCTT

  The gain-of-function MYD88 L265P mutation strongly promotes WM cell growth and survival through downstream activation of the above-mentioned pathways, with the transcription of NF-B. […] The MYD88 L265P mutation has been detected in 86% of sporadic WM cases and in all familial WM cases. […] In addition to the L265P mutation of MYD88, mutation of the C-X-C chemokine receptor type 4 (CXCR4) was found in 29% of patients with WM. […] The somatic CXCR4 mutations found in WM are similar to germline mutations in CXCR4 described in the rare warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. […] CXCR4 WHIM mutations lead to permanent activation of CXCR4 by its ligand stromal cell-derived factor 1/C-X-C motif chemokine ligand 12 (CXCL12), stimulate the proliferation, migration, and homing of WM cells to bone marrow niches, and therefore promote cell survival. […] The CXCR4 WHIM mutations seem to mediate drug resistance and have been shown to affect response to novel treatments, such as Brutons tyrosine kinase (BTK), mammalian target of rapamycin, and phosphoinositide 3-kinase (PI3K) inhibitors, as described below.

• #19 Waldenstrom Macroglobulinemia: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/207097-overview

  Treon et al reported that somatic mutations in MYD88 and CXCR4 in patients with Waldenstrm macroglobulinemia are determinants of clinical presentation and overall survival. Patients with MYD88 (L265P) and CXCR4 with warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome/nonsense (NS) mutations had significantly higher bone marrow disease involvement and symptomatic disease requiring therapy, including hyperviscosity syndrome. […] Patients with MYD88 (L265P) and WHIM/frameshift (FS) CXCR4 mutations or wild type CXCR4 had intermediate bone marrow involvement, while those with wild type MYD88 and CXCR4 had the lowest bone marrow disease burden. Risk of death was not affected by CXCR4 mutation status, but was markedly increased by wild type MYD88 status (hazard ratio 10.54).

• #20

  https://haematologica.org/article/view/6396

  A causal relationship between MGUS/WM and chronic antigenic stimulation has been suggested by the results of several studies. […] The low rate of proliferation of malignant WM cells was historically a major obstacle in the study of the genetic basis of WM, and this has only been surpassed in recent years with the incorporation of techniques focused on the study of interphase nuclei. […] While knowledge of the genetic basis of WM remains fragmented, understanding of the genetic landscape has significantly improved in recent years. […] The presence of 6q deletion may have prognostic significance, although some controversy remains. […] While the clinical implications of trisomy 4 are not well understood, it has been suggested that 4q may play a role in increased susceptibility to WM. […] The last decade has seen a marked evolution in our knowledge of the molecular basis of WM pathogenesis. […] Molecular pathways such as MYD88-IRAK4, NF-B and Akt-mTOR are promising avenues in the search for novel therapies.

• #21 Diagnostics in Waldenström’s macroglobulinemia: a consensus statement of the European Consortium for Waldenström’s Macroglobulinemia | Leukemia

  https://www.nature.com/articles/s41375-022-01762-3

  WM presents with a median of 23 chromosomal abnormalities per patient. Deletion of 6q (6q or del6q) is the most frequent chromosomal abnormality (40-50% of patients) and it is directly related with progression from asymptomatic to symptomatic WM. Deletion of 17p/TP53 is present in 8-15% of WM patients, and TP53 mutations are present in a small subset of patients with poor prognosis.

• #22 Waldenström Macroglobulinemia: Mechanisms of Disease Progression and Current Therapies

  https://www.mdpi.com/1422-0067/23/19/11145

  Waldenströms macroglobulinemia is an indolent, B-cell lymphoma without a known cure. The bone marrow microenvironment and cytokines both play key roles in Waldenströms macroglobulinemia (WM) tumor progression. […] The most frequently observed cytogenetic abnormality in WM is deletion of the long arm of chromosome 6 (6q). This deletion is correlated with poor prognostic features, such as higher levels of beta2-microglobulin and a greater prevalence of hypoalbuminemia and anemia. […] Deletion of the 6q chromosome appears to be the most common abnormality in WM, occurring in up to 50% of patients. […] Copy number changes were identified in nearly 80% of WM cases, notably the inactivation of TNFAIP3 and TRAF3, which are genes involved in the regulation of the NF-kB signaling pathway. […] More recently, whole-genome sequencing of 30 patients with WM was performed and the MYD88L265P somatic variant was identified in all patients with positive family history and 86% of sporadic cases.

• #23 How to manage Waldenstrom’s macroglobulinemia | Leukemia

  https://www.nature.com/articles/leu201336

  Waldenstroms macroglobulinemia (WM) is very distinct from other indolent lymphoma subtypes: by definition it is accompanied by a monoclonal IgM gammopathy; it presents always with bone marrow infiltration and often with clinical symptoms such as neuropathy or hyperviscosity. […] To this end, we still do not understand the cellular and molecular mechanisms that lead to the development of WM. […] Deletion of the long arm of chromosome 6 (6q) is the most frequent cytogenetic abnormality in WM, which is detectable in 7% by conventional cytogenetics and in 34% when analyzed by fluorescence in situ hybridization. […] At the genomic level, copy number alterations were identified in nearly 80% of cases, among them biallelic inactivation of TNFAIP3 and TRAF3, genes involved in the regulation of the nuclear factor-B signaling pathway.

• #24 Waldenström’s macroglobulinemia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Waldenstr%C3%B6m%27s_macroglobulinemia_pathophysiology

  Three most common epigenetic causes are: DNA methylation, histone acetylation, and non-coding RNAs such as miRNAs. […] Upregulation of miRNAs 155, 184, 206, 363, 494, and 542-3p occurs in Waldenstrm macroglobulinemia; among which miRNA-155 has a crucial role in tumor cell growth and proliferation in Waldenstrm macroglobulinemia.

• #25 Bing Center for Waldenstrom’s Macroglobulinemia – Genomics, Signaling and Treatment of Waldenström’s Macroglobulinemia

  https://www.waldenstroms.com/?view=article&id=417&catid=23

  The presence of mutated MYD88 in cerebrospinal fluid (fluid that bathes the brain and spinal column), as well pleuritic fluid (fluid that bathes the lining of the lungs) in WM patients has also permitted diagnostic and treatment implementation in patients with symptomatic disease outside of the bone marrow and lymph nodes. […] Somatic activating mutations in the C-terminal domain of the CXCR4 gene are also present in up to 40% of WM patients, and are nearly always observed in conjunction with MYD88 mutations in WM patients. […] The subclonal nature of CXCR4 mutations relative to MYD88 suggests that these mutations occur after MYD88, though could occur early in WM pathogenesis given their detection in IgM MGUS patients. […] The presence of ARID1A mutations, along with recurrent ARID1B deletions suggests that epigenetic dysregulation is likely to be present in WM, and further investigation is therefore warranted.

• #26

  https://journals.lww.com/co-hematology/fulltext/2011/07000/new_insights_into_the_pathogenesis_and_treatment.11.aspx

  Waldenstrom macroglobulinemia is a distinct low-grade lymphoproliferative disease. There have been recent significant advances in understanding the underlying pathogenesis of this disease, including genetic and epigenetic regulators of tumor progression. […] Current studies have shown that the tumor microenvironment plays a critical role in cell proliferation, dissemination, and drug resistance. […] This review provides an update of the advances in the pathogenesis of factors both intrinsic (in the tumor clone) and extrinsic (in the bone marrow microenvironment) that regulate tumor progression in Waldenstrom macroglobulinemia.

• #27 Waldenström Macroglobulinemia: Mechanisms of Disease Progression and Current Therapies

  https://www.mdpi.com/1422-0067/23/19/11145

  The tumor microenvironment has recently become an emerging area of research, with a growing number of studies looking at the tumor microenvironment in not only WM but in other cancers as well. […] IL-21 is a type I cytokine commonly found in the WM tumor microenvironment that rapidly induces the phosphorylation of STAT3 in WM cells. […] In WM, the expression of FGFR3 on CD19+ cells from WM patients was greater than the expression on B cells from healthy subjects, and FGFR3 was also overexpressed in the cell lines BCWM.1 and MEC-1. […] In WM, constitutive activation of the PI3K/Akt pathway exists and leads to increased cell proliferation and resistance to apoptosis. […] The role of bone marrow stromal cells has been extensively studied in WM and are attributed to the growth of WM cells.

• #28 Molecular pathogenesis of Waldenström’s macroglobulinemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3436227/

  A causal relationship between MGUS/WM and chronic antigenic stimulation has been suggested by the results of several studies. […] While genetic analysis has helped distinguish entities across B-cell neoplasms, there are nevertheless similarities in presentation. […] Molecular analysis has been increasingly used to analyze the biological basis and progression of WM, yet we still do not completely understand the genetic origins and active pathways of WM. […] The PI3/Akt pathway regulates cell survival, increasing proliferation while inhibiting apoptosis. […] The JAK/Stat pathway is a critical cytokine-initiated cascade that uses several STAT proteins to achieve normal physiological and biological function, including hematopoiesis. […] The continuous study of these dysfunctional pathways in WM will help provide targeted therapies.

• #29 Waldenström Macroglobulinemia: Mechanisms of Disease Progression and Current Therapies

  https://www.mdpi.com/1422-0067/23/19/11145

  Ephrin-B2 was demonstrated to be highly expressed on endothelial cells from the bone marrow of patients with WM compared with healthy controls. […] The presence of MYD88 L265P has also been reported in IgM MGUS, mucosa-associated lymphoid tissue lymphoma (9%), and diffuse large B-cell lymphoma. […] Hypoxia plays an important role in the progression of many malignancies and activated hypoxia pathways are strongly associated with adverse prognosis in cancer. […] The epithelial–mesenchymal transition (EMT) describes a process in which epithelial cells lose their epithelial characteristics and gain a mesenchymal phenotype. […] In WM patient samples, the Eph-B2 receptor was found to be overexpressed in WM cells. […] The management of WM has advanced tremendously with recent genomic findings that can help guide treatment approaches.

• #30 Single-cell profiles reveal tumor cell heterogeneity and immunosuppressive microenvironment in Waldenström macroglobulinemia | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03798-6

  Waldenstrm macroglobulinemia (WM) is a rare and incurable indolent B-cell malignancy. The molecular pathogenesis and the role of immunosuppressive microenvironment in WM development are still incompletely understood. […] Our data uncovered the heterogeneity of malignant cells in WM, and investigated the kinetic co-evolution of WM and immune cells, which played pivotal roles in disease development and progression. […] Based on the findings of T cell marker aberrant expressed on WM tumor cells, we speculate the long-time activation of tumor antigen-induced immunosuppressive microenvironment that is involved in the pathogenesis of WM. […] The mechanisms underlying the pathogenesis as well as the cellular origin of WM remain poorly understood. […] Our study facilitates further understanding of the biological heterogeneity of tumor cells and immunosuppressive microenvironment in WM.

• #31 Single-cell profiles reveal tumor cell heterogeneity and immunosuppressive microenvironment in Waldenström macroglobulinemia | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03798-6

  These findings indicate that tumor cell architecture involves in the malignant transformation, and the plasma cell differentiation was impaired in patients with higher malignant B cell infiltration. […] Our results showed malignant cells highly expressed immune checkpoint molecules CD47 and CD48, and strongly interacted with pre-exhausted T cells via CD47-LGALS9 and CD47-SIRPG molecules. […] These findings suggested that CD47 molecule played important roles in the process of immune escape of WM via triggering CD8+ T cell exhaustion. […] Our data demonstrated that the optional treatment for WM is needed to rapidly eliminate malignant B cells. […] This integrative analysis clarifies a comprehensive understanding of tumor cell heterogeneity and the altered functional states of immune cells in WM, which may have implications for the development of novel therapies.

• #32 Waldenstrom’s macroglobulinemia/lymphoplasmacytic lymphoma (Chapter 15) – Myeloma

  https://www.cambridge.org/core/books/myeloma/waldenstroms-macroglobulinemialymphoplasmacytic-lymphoma/BFCCC4A03EE968F001BE5AFF3417BDF1

  Waldenstroms macroglobulinemia (WM) is a distinct clinicopathological entity resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphocytes, lymphoplasmacytic cells and plasma cells which secrete a monoclonal IgM protein. […] Genetic factors appear to be important to the pathogenesis of WM. A common predisposition for WM with other malignancies has been raised, and there have been numerous reports of familiar predisposition, including clustering of family members with WM and other B cell lymphoproliferative diseases. […] Frequent familiar association with other immunological disorders in healthy relatives, including hypogammaglobulinemia and hypergammaglobulinemia (particularly polyclonal IgM), autoantibody (particularly to thyroid) production, and manifestation of hyper-responsive B cells have also been reported.

• #33 Waldenström macroglobulinemia – Wikipedia

  https://en.wikipedia.org/wiki/Waldenstr%C3%B6m_macroglobulinemia

  Waldenstrm macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. The most commonly associated mutations, based on whole-genome sequencing of 30 patients, are a somatic mutation in MYD88 (90% of patients) and a somatic mutation in CXCR4 (27% of patients). CXCR4 mutations cause symptomatic hyperviscosity syndrome and high bone marrow activity characteristic of the disease. However, CXCR4 mutation is not associated with splenomegaly, high platelet counts, or different response to therapy, questioning the relevance of CXCR4 in treating patients. An association has been demonstrated with the locus 6p21.3 on chromosome 6. […] There are genetic factors with first-degree relatives of Waldenstrm macroglobulinemia patients shown to have a highly increased risk of also developing the disease. There is also evidence to suggest that environmental factors, including exposure to farming, pesticides, wood dust, and organic solvents, may influence the development of Waldenstrm macroglobulinemia.

• #34 Lymphoplasmacytic lymphoma and Waldenström’s macroglobulinaemia | Lymphoma Action

  https://lymphoma-action.org.uk/types-lymphoma-non-hodgkin-lymphoma/lymphoplasmacytic-lymphoma-and-waldenstroms-macroglobulinaemia

  WM is a rare type of lymphoma. Fewer than 400 people are diagnosed with WM in the UK each year. […] Scientists dont know what causes WM. Some infections, inflammatory conditions or autoimmune diseases (diseases that happen when your immune system attacks your own body) such as Sjgren syndrome might increase your chance of developing WM. […] Many people with WM have symptoms caused by high levels of abnormal IgM antibody in their blood. This can make blood thicker than usual. This is called hyperviscosity. […] If your blood becomes too thick because of high levels of IgM, you might need to have it thinned by a procedure called plasmapheresis (plasma exchange). […] Researchers are continually trying to find out which treatment, or combination of treatments, works best for WM.

• #35 Waldenström macroglobulinemia: diagnosis and treatment | Giannopoulos | Hematology in Clinical Practice

  https://journals.viamedica.pl/hematology_in_clinical_practice/article/view/HCP.a2022.0014/70276

  Waldenstrm macroglobulinemia (WM), according to the 2017 World Health Organization classification, is defined as the co-occurrence of lymphoplasmacytic lymphoma involving the bone marrow with monoclonal gammopathy of the IgM class regardless of the concentration of monoclonal protein. […] Diagnostic characteristics in WM have changed significantly with the discovery of two molecular markers: MYD88 and CXCR4. The mutational status of these markers both affects clinical presentation and has shown therapeutic implications. […] The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. […] Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. […] The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s Macroglobulinemia.

• #36 Waldenström macroglobulinemia: diagnosis and treatment | Giannopoulos | Hematology in Clinical Practice

  https://journals.viamedica.pl/hematology_in_clinical_practice/article/view/HCP.a2022.0014

  Waldenstrm macroglobulinemia (WM), according to the 2017 World Health Organization classification, is defined as the co-occurrence of lymphoplasmacytic lymphoma involving the bone marrow with monoclonal gammopathy of the IgM class regardless of the concentration of monoclonal protein. […] Diagnostic characteristics in WM have changed significantly with the discovery of two molecular markers: MYD88 and CXCR4. The mutational status of these markers both affects clinical presentation and has shown therapeutic implications. […] A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstrm macroglobulinemia. […] Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia.

• #37 Current Therapeutic Options in Waldenstrom Macroglobulinemia

  https://touchoncology.com/haematological-malignancies/journal-articles/current-therapeutic-options-in-waldenstrom-macroglobulinemia/

  Alternations in the C-terminal of the CXCR4 gene account for the second most common somatic mutations in WM, and are observed in 30-40% of patients. […] The mutations in the C-terminal region leave the ligand binding region of the CXCR4 receptor intact and prevent internalization of the receptor upon binding with the SDF1 ligand. This results in sustained downstream signaling through the AKT, extracellular signal-regulated kinase (ERK) and BTK pathways. […] Patients with CXCR4WHIM/NS mutations present with a higher degree of marrow lymphoplasmacytosis compared to CXCR4WHIM/FS and CXCR4WT mutations. […] The presence of these mutations however does not have an unfavorable impact on OS. Therefore, the utility of evaluating them in the routine clinical practice is currently unclear outside of patients treated in clinical trials or with BTK inhibitors.

• #38 New Advances in Waldenström Macroglobulinemia

  https://www.onclive.com/view/new-advances-in-waldenstr-m-macroglobulinemia

  WM is characterized by MYD88 and CXCR4 mutations, affecting clinical presentation and treatment response. […] Recurrent somatic mutations in MYD88 and CXCR4 are observed in approximately 90% and 40% of patients with cancer, respectively, and give the malignant cells a survival advantage through apoptosis escape mechanisms. […] The genomic profile impacts the clinical presentation of patients with WM. For example, patients with CXCR4-mutated disease typically present with high serum IgM levels, symptomatic hyperviscosity, and acquired von Willebrand disease. […] In contrast, patients with MYD88 wild-type disease have a higher risk of an aggressive transformation and experience inferior survival outcomes. […] The asymptomatic WM risk scoring system uses the percentage of bone marrow involvement, serum IgM, albumin, and beta-2-microglobulin levels to identify patients at high, intermediate, and low risk of needing therapy.

• #39 Novel Approaches in Waldenström’s Macroglobulinemia | Dana-Farber Cancer Institute

  https://www.dana-farber.org/for-physicians/clinical-resources/hematologic-malignancies/advances-newsletter/2025-issue-20/novel-approaches-in-waldenstroms-macroglobulinemia

  Waldenstrm’s macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by the malignant accumulation of IgM-producing lymphoplasmacytic cells in the bone marrow and other organs. Recurrent somatic mutations in MYD88 and CXCR4 give the malignant cells a survival advantage through an apoptosis escape mechanism (i.e., immortalization). […] Approximately 80% of Waldenstrm’s macroglobulinemia patients with asymptomatic WM will require therapy within ten years of diagnosis. […] Chemoimmunotherapy regimens are commonly used with a long track record and evidence of durable responses. Proteasome inhibitors can also be used combined with rituximab. Over the last decade and based on research developed at the Bing Center for Waldenstrm’s Macroglobulinemia, Bruton tyrosine kinase (BTK) inhibitors have become a standard treatment option, supported by the approval of ibrutinib (with or without rituximab) and zanubrutinib by the Food and Drug Administration to treat WM in recent years. Beyond chemoimmunotherapy and BTK inhibitors, BCL2 antagonists such as venetoclax and non-covalent BTK inhibitors such as pirtobrutinib are safe and effective options. […] Given Waldenstrm’s macroglobulinemia rarity, clinical trials are essential to advance the field, and multi-institutional collaboration is crucial.

• #40 Waldenström macroglobulinemia: diagnosis and treatment | Giannopoulos | Hematology in Clinical Practice

  https://journals.viamedica.pl/hematology_in_clinical_practice/article/view/HCP.a2022.0014

  The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s Macroglobulinemia. […] The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis.

• #41 Molecular pathogenesis of Waldenström’s macroglobulinemia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3436227/

  While emerging technologies have provided greater insight into genetic abnormalities observed in patients with WM, further biological studies and molecular analysis are challenged by the limited number of viable cellular models proven to be derived from WM tumors. […] The last decade has seen a marked evolution in our knowledge of the molecular basis of WM pathogenesis. […] Molecular pathways such as MYD88-IRAK4, NF-B and Akt-mTOR are promising avenues in the search for novel therapies.

• #42 New Advances in Waldenström Macroglobulinemia

  https://www.onclive.com/view/new-advances-in-waldenstr-m-macroglobulinemia

  On the other hand, BTK inhibitors are associated with unique adverse events, such as an increased risk of bleeding, hypertension, and arrhythmia. […] Clinical trials for special WM populations include a phase 2 study evaluating the combination of acalabrutinib and rituximab for patients with IgM monoclonal gammopathy of undetermined significance or WM with predominantly demyelinating neuropathy. […] Given WM’s rarity, clinical trials are essential to advance the field, and multi-institutional collaboration is crucial.

• #43 Nucleic Acid Biomarkers in Waldenström Macroglobulinemia and IgM-MGUS: Current Insights and Clinical Relevance

  https://www.mdpi.com/2075-4418/12/4/969

  Moreover, WGS identified several other highly prevalent somatic mutations in CXCR4 (CXCR4WHIM or CXCR4MUT) and ARID1A genes. […] Besides mutational profile, different classes of coding and non-coding RNA have also increasingly been investigated as these molecules may have crucial roles in disease onset and progression by regulating gene expression and cellular function, and may serve as potential biomarkers. […] In recent years, liquid biopsy has been proposed as an alternative to invasive tissue biopsy. […] The development and use of circulating, reliable biomarkers through liquid biopsy sampling for the diagnosis, therapy response prediction and prognostication of WM could significantly impact daily clinical practice. […] This review aims to present current knowledge regarding nucleic acid biomarkers in WM and IgM-MGUS to elucidate their role and highlight their translational potential as precision medicine biomarkers.

Zobacz więcej