MYD88 mutated and wild-type Waldenstrom's Macroglobulinemia: characterization of chromosome 6q gene losses and their mutual exclusivity with mutations in CXCR4.
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ABSTRACT:
SUBMITTER: Guerrera ML
PROVIDER: S-EPMC6119142 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
Publications
<i>MYD88</i> mutated and wild-type Waldenström's Macroglobulinemia: characterization of chromosome 6q gene losses and their mutual exclusivity with mutations in <i>CXCR4</i>.
Guerrera Maria Luisa ML Tsakmaklis Nickolas N Xu Lian L Yang Guang G Demos Maria M Kofides Amanda A Chan Gloria G GG Manning Robert J RJ Liu Xia X Chen Jiaji G JG Munshi Manit M Patterson Christopher J CJ Castillo Jorge J JJ Dubeau Toni T Gustine Joshua J Carrasco Ruben D RD Arcaini Luca L Varettoni Marzia M Cazzola Mario M Treon Steven P SP Hunter Zachary R ZR
Haematologica 20180329 9
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Project description:Recurrent mutations affecting MYD88 and CXCR4 gene nowadays form the basis for the diagnosis, risk stratification and use of inhibitors targeting these signalling pathways in LPL/WM which are rare B cell neoplasms. MYD88 L265P mutation analysis was performed on 33 cases of LPL/WM by AS-PCR (positivity-84.8%, n = 28/33) and by Sanger sequencing (positivity-39.3%, n = 13/33). We had only two cases with CXCR4 non-sense (NS) mutation (p.S338*) using Sanger sequencing. MYD88 (L265P) mutation detection by AS-PCR can form reliable biomarker for the diagnosis of LPL/WM in molecular labs. Although the cohort is small, still the CXCR4 mutation frequency in our study is low as compared to the published literature.
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Project description:BackgroundWaldenström macroglobulinemia (WM) is a rare, indolent B-cell lymphoma. Clinically, chromosome 6q deletion (6q del) including loss of the B lymphocyte-induced maturation protein 1 gene (BLIMP-1) is reported to be associated with poor prognosis. However, it remains unclear how the underlying biological mechanism contributes to the aggressiveness of WM with 6q del.MethodsHere, we conducted oligonucleotide microarray analysis to clarify the differences in gene expression between WM with and without 6q del. Gene ontology (GO) analysis was performed to identify the main pathways underlying differences in gene expression. Eight bone marrow formalin-fixed paraffin-embedded samples of WM were processed for interphase fluorescence in situ hybridization analysis, and three were shown to have 6q del.ResultsGO analysis revealed significant terms including "lymphocyte activation" (corrected p value=6.68E-11), which included 31 probes. Moreover, IL21R and JAK3 expression upregulation and activation of the B-cell receptor signaling (BCR) pathway including CD79a, SYK, BLNK, PLCγ2, and CARD11 were detected in WM with 6q del compared with WM without 6q del.ConclusionThe present study suggested that the BCR signaling pathway and IL21R expression are activated in WM with 6q del. Moreover, FOXP1 and CBLB appear to act as positive regulators of the BCR signaling pathway. These findings might be attributed to the aggressiveness of the WM with 6q del expression signature.
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