Epigenomics in Waldenström macroglobulinemia

Hunter, Zachary; Treon, Steven P.

doi:10.1182/blood.2020006244

Cited by 6 publications

(8 citation statements)

References 8 publications

(13 reference statements)

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“…Expression differences in LYN may therefore be related to epigenomic (methylation) changes that accompany CXCR4 mutation status and tumor differentiation. 17,18 Indeed, lower expression levels of LYN were observed in healthy donor plasma cells (Supplemental Figure 1A) consistent with the known down-regulation of BCR pathway that accompanies B-cell to plasma cell differentiation. As MYD88 MUT CXCR4 WT versus MYD88 MUT CXCR4 MUT WM cells show more advanced plasmacytic differentiation, the finding of lower LYN expression in this subgroup is not surprising.…”

Section: P-lyn Expression Is Downregulated In Myd88 Wm Cellssupporting

confidence: 72%

“…As MYD88 MUT CXCR4 WT versus MYD88 MUT CXCR4 MUT WM cells show more advanced plasmacytic differentiation, the finding of lower LYN expression in this subgroup is not surprising. 15,18 Importantly, the lack of SFK LYN activity observed in primary MYD88 MUT WM samples (including one that was CXCR4 MUT ) suggests that LYN is unlikely to mediate SYK activation in MYD88 Leu265Pro WM but may be its driver in MYD88 Leu265Pro DLBCL cells due to chronic active BCR signaling. 9…”

Section: P-lyn Expression Is Downregulated In Myd88 Wm Cellsmentioning

confidence: 99%

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A new role for the SRC family kinase HCK as a driver of SYK activation in MYD88 mutated lymphomas

Munshi¹,

Liu²,

Kofides³

et al. 2022

Blood Advances

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The SRC family kinase (SFK) HCK is transcriptionally upregulated and activated by mutated MYD88 (MYD88Mut), a key adaptor for Toll-receptor signaling. HCK activates BTK, AKT and ERK in MYD88Mut lymphomas. SYK, a BCR component is activated in MYD88Mut lymphoma cells. While the SFK LYN serves as a trigger for SYK activation in MYD88Mut ABC DLBCL cells, LYN activity is muted in MYD88Mut WM cells. We therefore investigated a role for HCK in mediating SYK activation. Over-expression of wild-type (HCKWT) or gatekeeper mutated (HCKThr333Met) HCK in MYD88Mut lymphoma cells triggered SYK activation. Conversely, HCK knockdown reduced p-SYK in MYD88Mut lymphoma cells. Co-immunoprecipitation experiments showed that HCK was complexed with p-SYK in MYD88Mut BCWM.1 and TMD8 cells, but not in MYD88 wild-type (WT) Ramos cells. Rescue experiments in MYD88Mut lymphoma cells expressing HCKThr333Met led to persistent HCK and SYK activation and resistance to the HCK inhibitor A419259. Treatment of primary MYD88Mut WM cells with A419259 reduced p-HCK and p-SYK expression. Taken together, our findings show that SYK is activated by HCK in MYD88Mut B-cell lymphomas cells; broaden the pro-survival signaling generated by aberrant HCK expression in response to MYD88Mut; and help define HCK as an important therapeutic target in MYD88Mut B-cell lymphomas.

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Section: P-lyn Expression Is Downregulated In Myd88 Wm Cellssupporting

confidence: 72%

Section: P-lyn Expression Is Downregulated In Myd88 Wm Cellsmentioning

confidence: 99%

A new role for the SRC family kinase HCK as a driver of SYK activation in MYD88 mutated lymphomas

Munshi¹,

Liu²,

Kofides³

et al. 2022

Blood Advances

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“…There is an overexpression of the VDJ recombination genes DNTT, RAG1, and RAG2, as well as increased expression of MYD88 and CXCR4 signaling genes in patients with WM [14,15] . Patients with WM have also been shown to have abnormal methylation patterns and distinct epigenomic signatures [16] . They exhibit a wide range of symptoms because of their distinctive bone marrow and/or organ infiltration by clonal cells, as well as their unique immunological and physiochemical features of monoclonal IgM.…”

Section: Introductionmentioning

confidence: 99%

Co‐Binding of JQ1 and Venetoclax Exhibited Synergetic Inhibitory Effect for Cancer Therapy; Potential Line of Treatment for the Waldenström Macroglobulinemia Lymphoma

Elamin

Aljoundi

Soliman

2022

Chemistry & Biodiversity

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In recent times, the development of combination therapy has been a focal point in drug discovery. This article explores the potential synergistic effect of co‐administration of Bcl2 inhibitor Venetoclax and BET inhibitor JQ1. We envisioned that the ‘dual‐site’‐binding of Bcl2 has significant prospects and paves the way for the next round of rational design of potent Waldenström macroglobulinemia (WM) therapy. The preferential binding mechanisms of the multi‐catalytic sites of the Bcl2 enzyme have been a subject of debate in the literature. This study conducted a systematic procedure to explore the preferred binding modes and the structural effects of co‐binding at each catalytic active site. Interestingly, a mutual enhanced binding effect was observed – Venetoclax increased the binding affinity of JQ1 by 11.5 %, while JQ1 boosted the binding affinity of Venetoclax by 16.3 % when compared with individual inhibition of each drug. This synergistic binding effect has significantly increased protein stability, with substantial correlated movements and multiple van der Waals interactions. The structural and thermodynamic insights unveiled in this report would assist the future design of improved combined therapy against WM.

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“…16,17 Patterns of aberrant methylation and unique epigenomics signatures have been also described in patients with WM. 18 The diverse clinical presentation of patients with WM is attributed to the diverse bone marrow and/or organ infiltration by clonal cells and the immunological and physiochemical properties of monoclonal IgM that are primarily present in each patient. It has to be noted that treatment will not be required at the time diagnosis in up to one third of patients.…”

Section: Introductionmentioning

confidence: 99%

“…16,17 Patterns of aberrant methylation and unique epigenomics signatures have been also described in patients with WM. 18…”

Section: Introductionmentioning

confidence: 99%

Current and novel BTK inhibitors in Waldenström’s macroglobulinemia

Ntanasis‐Stathopoulos

Gavriatopoulou

Fotiou

et al. 2021

Therapeutic Advances in Hematology

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The current therapeutic approach in Waldenström’s macroglobulinemia (WM) is being driven by insights in disease biology and genomic landscape. Bruton’s tyrosine kinase (BTK) plays a key role in signaling pathways for the survival of WM clone. BTK inhibition has changed the treatment landscape of the disease. Ibrutinib has resulted in deep and durable responses both as an upfront and salvage treatment with a manageable toxicity profile. However, the need for fewer off-target effects and deeper responses has resulted in the clinical development of second-generation BTK inhibitors. Zanubrutinib has resulted in clinically meaningful antitumor activity, including deep and durable responses, with a low discontinuation rate due to treatment-related toxicities. Cardiovascular adverse events seem to be milder compared with ibrutinib. Interestingly, the efficacy of zanubrutinib in WM is significant both for MYD88L265P and MYD88WT patients. Although the randomized, phase III ASPEN clinical trial did not meet its primary endpoint in terms of showing a superiority of zanubrutinib in deep responses compared with ibrutinib, secondary efficacy and safety endpoints underscore the potential clinical role of zanubrutinib in the treatment algorithm of WM independent of the MYD88 mutational status. Combination regimens and non-covalent BTK inhibitors are emerging as promising treatment strategies. Long-term data will determine whether next-generation BTK inhibitors are more potent and safer compared with ibrutinib, and whether they are able to overcome resistance to ibrutinib, either alone or in combination with inhibitors of other interrelated molecular pathways.

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Epigenomics in Waldenström macroglobulinemia

Cited by 6 publications

References 8 publications

A new role for the SRC family kinase HCK as a driver of SYK activation in MYD88 mutated lymphomas

A new role for the SRC family kinase HCK as a driver of SYK activation in MYD88 mutated lymphomas

Co‐Binding of JQ1 and Venetoclax Exhibited Synergetic Inhibitory Effect for Cancer Therapy; Potential Line of Treatment for the Waldenström Macroglobulinemia Lymphoma

Current and novel BTK inhibitors in Waldenström’s macroglobulinemia

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