SF3B1and Other Novel Cancer Genes in Chronic Lymphocytic Leukemia

Abstract

Background The somatic genetic basis of chronic lymphocytic leukemia, a common and clinically heterogeneous leukemia occurring in adults, remains poorly understood. Methods We obtained DNA samples from leukemia cells in 91 patients with chronic lymphocytic leukemia and performed massively parallel sequencing of 88 whole exomes and whole genomes, together with sequencing of matched germline DNA, to characterize the spectrum of somatic mutations in this disease. Results Nine genes that are mutated at significant frequencies were identified, including four with established roles in chronic lymphocytic leukemia (TP53 in 15% of patients, ATM in 9%, MYD88 in 10%, and NOTCH1 in 4%) and five with unestablished roles (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X). SF3B1, which functions at the catalytic core of the spliceosome, was the second most frequently mutated gene (with mutations occurring in 15% of patients). SF3B1 mutations occurred primarily in tumors with deletions in chromosome 11q, which are associated with a poor prognosis in patients with chronic lymphocytic leukemia. We further discovered that tumor samples with mutations in SF3B1 had alterations in pre–messenger RNA (mRNA) splicing. Conclusions Our study defines the landscape of somatic mutations in chronic lymphocytic leukemia and highlights pre-mRNA splicing as a critical cellular process contributing to chronic lymphocytic leukemia.

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

“…Probes targeting all coding exons or hotspot regions of 27 known CLL driver genes and/or genes previously reported in EGR2-mutated CLL 19,29,[37][38][39][40][41][42][43][44] were designed using Agilent"s SureDesign service (https://earray.chem.agilent.com/suredesign/home.htm, Supplemental Table S4). …”

Next generation RNA‐sequencing in prognostic subsets of chronic lymphocytic leukemia

“…MSI2 has been shown to regulate normal hematopoiesis and promote aggressive chronic myeloid leukemia [9]. Interestingly, mutations in splicing machinery genes were recently reported as common events in CLL [10], although the correlation between these mutations and subset-specific gene splice-variants requires further investigation.For the next step, we explored ncRNA expression and found that 109 transcripts of previously annotated RNA (suggested or confirmed) were differentially expressed between subset #1 and #4 (Supporting Information Table 5S). Two such examples, SNORD48 ( Fig.…”

Lymphoma classification and the tools of our trade: an introduction to the 2012 USCAP Long Course

“…While the ultimate technologies to be utilized remain to be established, as discussed by E Campo in this journal, 33 many discoveries are being made, particularly as whole genome/exome sequencing is being explored by many. [33][34][35][36][37] While for some entities, such as chronic lymphocytic leukemia, the mutations being discovered are each present in a relatively small proportion of cases, they may still be of great biological and clinical interest with therapeutic implications. 33,[35][36][37] Detection of other mutations may be useful for diagnostic purposes, being present in a high proportion of a specific type of lymphoid neoplasm.…”

“…[33][34][35][36][37] While for some entities, such as chronic lymphocytic leukemia, the mutations being discovered are each present in a relatively small proportion of cases, they may still be of great biological and clinical interest with therapeutic implications. 33,[35][36][37] Detection of other mutations may be useful for diagnostic purposes, being present in a high proportion of a specific type of lymphoid neoplasm. For example, it has been learned only recently that hairy cell leukemia but very few other B-cell neoplasms have BRAF V600E mutations.…”