Genomic Landscape of Waldenstrom Macroglobulinemia and Its Impact on Treatment Strategies.
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ABSTRACT:
SUBMITTER: Treon SP
PROVIDER: S-EPMC7351339 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Activating MYD88 mutations are present in 95% of Waldenström macroglobulinemia (WM) patients, and trigger NF-?B through BTK and IRAK. The BTK inhibitor ibrutinib is active in MYD88-mutated (MYD88 MUT ) WM patients, but shows lower activity in MYD88 wild-type (MYD88 WT ) disease. MYD88 WT patients also show shorter overall survival, and increased risk of disease transformation in some series. The genomic basis for these findings remains to be clarified. We performed whole exome and transcriptome sequencing of sorted tumor samples from 18 MYD88 WT patients and compared findings with WM patients with MYD88 MUT disease. We identified somatic mutations predicted to activate NF-?B (TBL1XR1, PTPN13, MALT1, BCL10, NFKB2, NFKBIB, NFKBIZ, and UDRL1F), impart epigenomic dysregulation (KMT2D, KMT2C, and KDM6A), or impair DNA damage repair (TP53, ATM, and TRRAP). Predicted NF-?B activating mutations were downstream of BTK and IRAK, and many overlapped with somatic mutations found in diffuse large B-cell lymphoma. A distinctive transcriptional profile in MYD88 WT WM was identified, although most differentially expressed genes overlapped with MYD88 MUT WM consistent with the many clinical and morphological characteristics that are shared by these WM subgroups. Overall survival was adversely affected by mutations in DNA damage response in MYD88 WT WM patients. The findings depict genomic and transcriptional events associated with MYD88 WT WM and provide mechanistic insights for disease transformation, decreased ibrutinib activity, and novel drug approaches for this population.
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Project description:Waldenström macroglobulinemia is often an indolent disorder, and many patients are candidates for observation with careful monitoring. For symptomatic patients, one must distinguish between those patients whose symptoms are related to immunologic manifestations associated with the IgM monoclonal protein and those that have symptoms related to progressive marrow and nodal infiltration with lymphoplasmacytic lymphoma. In Waldenström macroglobulinemia, the driver for therapy in the majority of patients is progressive anemia, secondary to bone marrow replacement by lymphoplasmacytic lymphoma. Recent introduction of MYD88 mutational analysis has been very useful for diagnostic purposes but is unclear what effect it might have on the prognosis or response rate to therapy. An algorithm is provided on the management of asymptomatic individuals and the sequence used for chemotherapeutic intervention of symptomatic patients.
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Project description:Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Waldenstrom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m(2) per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n = 1), partial response (n = 15), and major response (n = 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P = .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalidomide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie, <or= 200 mg/day) should be considered given the high frequency of treatment-related neuropathy in this patient population. This trial is registered at www.clinicaltrials.gov as #NCT00142116.
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Project description:The management of Waldenström macroglobulinemia (WM) has evolved tremendously with recent genomic discoveries that correlate with clinical presentation and could help to tailor treatment approaches. The current diagnosis of WM requires clinicopathological criteria, including bone marrow involvement by lymphoplasmacytic lymphoma cells, a serum immunoglobulin M (IgM) monoclonal paraprotein, and presence of the MYD88 L265P mutation. Once the diagnosis is established, the relationship between the patient's symptoms and WM should be carefully investigated, because therapy should be reserved for symptomatic patients. Bone marrow involvement and serum levels of IgM, albumin, and ?2-microglobulin can be used to estimate the time until treatment initiation. The treatment of WM patients should be highly personalized, and the patient's clinical presentation, comorbidities, genomic profile, and preferences, as well as toxicity of the treatment regimens, should be taken into account. Alkylating agents (bendamustine, cyclophosphamide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), anti-CD20 monoclonal antibodies (rituximab, ofatumumab), and Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are safe and highly effective treatment options in patients with WM. Because novel covalent and noncovalent BTK inhibitors (tirabrutinib, vecabrutinib, LOXO-305, ARQ-531), BCL2 antagonists (venetoclax), and CXCR4-targeting agents (ulocuplumab, mavorixafor) are undergoing clinical development in WM, the future of WM therapy certainly appears bright and hopeful.
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Project description:Whole-genome sequencing has identified highly prevalent somatic mutations including MYD88, CXCR4, and ARID1A in Waldenström macroglobulinemia (WM). The impact of these and other somatic mutations on transcriptional regulation in WM remains to be clarified. We performed next-generation transcriptional profiling in 57 WM patients and compared findings to healthy donor B cells. Compared with healthy donors, WM patient samples showed greatly enhanced expression of the VDJ recombination genes DNTT, RAG1, and RAG2, but not AICDA Genes related to CXCR4 signaling were also upregulated and included CXCR4, CXCL12, and VCAM1 regardless of CXCR4 mutation status, indicating a potential role for CXCR4 signaling in all WM patients. The WM transcriptional profile was equally dissimilar to healthy memory B cells and circulating B cells likely due increased differentiation rather than cellular origin. The profile for CXCR4 mutations corresponded to diminished B-cell differentiation and suppression of tumor suppressors upregulated by MYD88 mutations in a manner associated with the suppression of TLR4 signaling relative to those mutated for MYD88 alone. Promoter methylation studies of top findings failed to explain this suppressive effect but identified aberrant methylation patterns in MYD88 wild-type patients. CXCR4 and MYD88 transcription were negatively correlated, demonstrated allele-specific transcription bias, and, along with CXCL13, were associated with bone marrow disease involvement. Distinct gene expression profiles for patients with wild-type MYD88, mutated ARID1A, familial predisposition to WM, chr6q deletions, chr3q amplifications, and trisomy 4 are also described. The findings provide novel insights into the molecular pathogenesis and opportunities for targeted therapeutic strategies for WM.
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Project description:Understanding the biology of Waldenström macroglobulinemia is hindered by a lack of preclinical models. We report a novel cell line, RPCI-WM1, from a patient treated for WM. The cell line secretes human immunoglobulin M (h-IgM) with ?-light chain restriction identical to the primary tumor. The cell line has a modal chromosomal number of 46 and harbors chromosomal changes such as deletion of 6q21, monoallelic deletion of 9p21 (CDKN2A), 13q14 (RB1) and 18q21 (BCL-2), with a consistent amplification of 14q32 (immunoglobulin heavy chain; IgH) identical to its founding tumor sample. The clonal relationship is confirmed by identical CDR3 length and single nucleotide polymorphisms as well as a matching IgH sequence of the cell line and founding tumor. Both also harbor a heterozygous, non-synonymous mutation at amino acid 265 in the MYD88 gene (L265P). The cell line expresses most of the cell surface markers present on the parent cells. Overall, RPCI-WM1 represents a valuable model to study Waldenström macroglobulinemia.
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Project description:Waldenström macroglobulinemia (WM) cells present with increased expression of microRNA-206 (miRNA-206) and reduced expression of miRNA-9*. Predicted miRNA-206- and -9*-targeted genes include histone deacetylases (HDACs) and histone acetyl transferases (HATs), indicating that these miRNAs may play a role in regulating histone acetylation. We were able to demonstrate that primary WM cells are characterized by unbalanced expression of HDACs and HATs, responsible for decreased acetylated histone-H3 and -H4, and increased HDAC activity. We next examined whether miRNA-206 and -9* modulate the aberrant expression of HDAC and HATs in WM cells leading to increased transcriptional activity. We found that restoring miRNA-9* levels induced toxicity in WM cells, supported by down-modulation of HDAC4 and HDAC5 and up-regulation of acetyl-histone-H3 and -H4. These, together with inhibited HDAC activity, led to induction of apoptosis and autophagy in WM cells. To further confirm that miRNA-9*-dependent modulation of histone acetylation is responsible for induction of WM cytotoxicity, a novel class of HDAC inhibitor (LBH589) was used; we confirmed that inhibition of HDAC activity leads to toxicity in this disease. These findings confirm that histone-modifying genes and HDAC activity are deregulated in WM cells, partially driven by the aberrant expression of miRNA-206 and -9* in the tumor clone.
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Project description: Not available
| S-EPMC6293872 | biostudies-literature
Project description:Waldenström macroglobulinemia (WM) is a rare, immunoglobulin M -associated lymphoplasmacytic lymphoma. With the recent discoveries of CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) and MYD88 mutations, our understanding of the biology of WM has expanded substantially. While WM still remains incurable, the field is rapidly evolving, and a number of promising agents with significant activity in this malignancy are being evaluated currently. In this review, we discuss the new developments that have occurred in WM over the past 15 years, with a focus on the role of ibrutinib, an oral Bruton's tyrosine kinase inhibitor that has recently been approved for WM in the United States, Europe, and Canada.
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Project description:Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.
| S-EPMC4148763 | biostudies-literature