Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia

Abstract

• Transcription profiles associated with mutated MYD88, CXCR4, ARID1A, abnormal cytogenetics including 6q2, and familial WM are described.• Mutated CXCR4 profiles show impaired expression of the tumor suppressor response induced by MYD88 L265P and also G-protein/MAPK inhibitors.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. (Blood. 2016;128(6):827-838)

Acquired mutations associated with ibrutinib resistance in Waldenström macroglobulinemia

“…12 Although TP53 mutations are rare in WM, and were not observed in any of the ibrutinibresistant patients in this series by targeted NGS (data not shown), dysregulated RAG1, RAG2, and ATM expression are commonly observed in WM. 23 Further insights into the role of these dysregulated genes, as well as other genomic or epigenomic variants that contribute to the acquisition of BTK C481 variants in WM patients on ibrutinib are needed. The findings may also indicate an increased susceptibility of CXCR4-mutated patients to develop BTK…”

Waldenström Macroglobulinemia: Review of Pathogenesis and Management

“…Surprisingly, patients with MYD88 L265P showed significantly worse OS compared to MYD88 WT patients despite their lower disease burden 52 . In a recent study comparing whole genome sequencing in 57 WM patients vs. healthy donors, MYD88 and CXCR4 expression levels were shown to be inversely correlated, which is also affected by mutation status 53 . In most of WM patients, DNTT, RAG1, and RAG2 that are involved in VDJ recombination and BCL2 were found to be highly upregulated, and BAX expression was low 53 .…”

“…In a recent study comparing whole genome sequencing in 57 WM patients vs. healthy donors, MYD88 and CXCR4 expression levels were shown to be inversely correlated, which is also affected by mutation status 53 . In most of WM patients, DNTT, RAG1, and RAG2 that are involved in VDJ recombination and BCL2 were found to be highly upregulated, and BAX expression was low 53 . Further, in comparison to MYD88 L265P , MYD88 WT patient showed increased expression of PI3K signaling genes, but low NFκB response genes as well as increase promoter methylation in PRDM5 and WNK2 genes 53 .…”

New developments in the management of Waldenström macroglobulinemia

“…Another recent article on the transcriptional profiling (RNAseq) and comparison of the WM patients to the normal population without B-cell disorders attempted to shed more light on this matter. Four genotypic groups as indicated in Table 1 are currently identifiable 16,17…”