Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia.
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.
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
Zachary R
0000-0002-1689-1691
ZR
Hunter
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Lian
L
Xu
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
Guang
G
Yang
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Nicholas
N
Tsakmaklis
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Josephine M
JM
Vos
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Xia
X
Liu
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Jie
J
Chen
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Robert J
RJ
Manning
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Jiaji G
JG
Chen
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Philip
P
Brodsky
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Christopher J
CJ
Patterson
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Joshua
J
Gustine
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
Toni
T
Dubeau
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
Jorge J
JJ
Castillo
Department of Medicine, Harvard Medical School, Boston, MA; Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA; and.
Kenneth C
KC
Anderson
Department of Medicine, Harvard Medical School, Boston, MA; Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA; and Department of Medicine, Boston VA Healthcare System, West Roxbury, MA.
Nikhil M
NM
Munshi
Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
Steven P
SP
Treon
D000328:Adult; D000368:Aged; D000483:Alleles; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D011401:Promoter Regions, Genetic; D019718:Receptors, CXCR4 / Q000235:genetics; D059467:Transcriptome; D060152:V(D)J Recombination; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics* / Q000473:pathology
C527276:CXCR4 protein, human; D053594:Myeloid Differentiation Factor 88; D019718:Receptors, CXCR4