Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

Abstract

Summary Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12 and del(13q)) or subclonal (e.g., SF3B1, TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two timepoints. Ten of 12 CLL cases treated with chemotherapy (but only 1 of 6 without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1, TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcome.

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

“…24 Furthermore, Mcl-1 expression is known to correlate with progressive disease, resistance to chemotherapy and time to first treatment 23 SSA-induced killing of CLL cells was independent of the mutational status of SF3B1 and IGHV, as well as, CD38 and ZAP70 expression. SF3B1 mutations have been shown to be present at sub-clonal levels, 50 however all our SF3B1 mutant samples exhibited deregulated splicing supporting the notion that the SF3B1 mutant protein in these cases has a functional impact. The equal sensitivity of CLL samples to SSA indicates a common mechanism of cell death irrespective of the size of the SF3B1 mutated clone within the population.…”

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). …”

The long‐term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years

“…The genomic landscape of patients before treatment is variable and often comprises a dominant clone together with one or more sub‐clones. Clonal evolution is more common after treatment than in untreated CLL (Landau et al , 2013) and small sub‐clones (e.g. TP53 ‐mutated sub‐clones not detected initially by conventional methods) can become predominant after relapse (Rossi et al , 2014; Sutton & Rosenquist, 2015).…”

“…TP53 ‐mutated sub‐clones not detected initially by conventional methods) can become predominant after relapse (Rossi et al , 2014; Sutton & Rosenquist, 2015). Further longitudinal genomic studies are required to determine whether therapies such as FC, which induce a powerful DNA damage response, select for small drug resistant clones that impair response to subsequent chemo or chemo‐immunotherapy (Rosenwald et al , 2004; Landau et al , 2013; Rossi et al , 2014). …”