De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways

Abstract

Despite the advent of tyrosine kinase inhibitors, a proportion of chronic myeloid leukemia patients in chronic phase fail to respond to imatinib or to second-generation inhibitors and progress to blast crisis. Until now, improvements in the understanding of the molecular mechanisms responsible for chronic myeloid leukemia transformation from chronic phase to the aggressive blast crisis remain limited. Here we present a large parallel sequencing analysis of 10 blast crisis samples and of the corresponding autologous chronic phase controls that reveals, for the first time, recurrent mutations affecting the ubiquitin-conjugating enzyme E2A gene ( UBE2A , formerly RAD6A ). Additional analyses on a cohort of 24 blast crisis, 41 chronic phase as well as 40 acute myeloid leukemia and 38 atypical chronic myeloid leukemia patients at onset confirmed that UBE2A mutations are specifically acquired during chronic myeloid leukemia progression, with a frequency of 16.7% in advanced phases. In vitro studies show that the mutations here described cause a decrease in UBE2A activity, leading to an impairment of myeloid differentiation in chronic myeloid leukemia cells.

Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease

“…RUNX1 is a frequent and aggressive driver of hematologic malignancies 15,[46][47][48] and has been described in multiple CML studies, but it is not always associated with poor outcome. [16][17][18][19][20][21][22] In our cohort, mutated RUNX1 was rarely detected as the sole mutated cancer gene. We speculate that in optimal responders to TKIs, certain leukemic clones with mutated genes at diagnosis may be eradicated by TKIs.…”

“…13 However, studies have demonstrated that transformation to blast crisis (BC) is due to the accumulation of genetic abnormalities detectable as additional cytogenetic changes and mutations in individual genes identified by deep sequencing. [14][15][16][17][18][19][20][21][22] Furthermore, gene expression changes may distinguish CP from BC and predict response to TKI therapy. [23][24][25][26][27] The increasingly mainstream use of next-generation sequencing for studying cancer genomes is advancing our understanding of disease pathogenesis and prognosis.…”

“…Many of the mutated genes have been identified in CML and other hematologic diseases. [15][16][17][18][19][20][21][22]29,36 However, some of the recurrent variants, mutated genes, fusions, and splice variants are novel in CML. We highlight the importance of incorporating multiple sequencing platforms to fully characterize the various mutation classes.…”

Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

“…Makishima et al screened Janus kinase (JAK)-2, CBL, CBLB, TET2, ASXL1, IDH1, and IDH2 coding sequences in 26 BP patients, identifying four TET2, two ASXL1, two IDH1/2, one CBL and one CBLB mutations in myeloid BP [94]. A whole exome sequencing analysis of 10 matched CP-BP samples has more recently uncovered that UBE2A mutations may recurrently (16.7% of cases in the validation cohort) be acquired at the time of progression [95]. Functional studies have revealed that mutations abrogate UBE2A activity, leading to an impairment of myeloid differentiation [95].…”

“…A whole exome sequencing analysis of 10 matched CP-BP samples has more recently uncovered that UBE2A mutations may recurrently (16.7% of cases in the validation cohort) be acquired at the time of progression [95]. Functional studies have revealed that mutations abrogate UBE2A activity, leading to an impairment of myeloid differentiation [95]. At present, the largest study taking advantage of an integrated approach of whole-exome sequencing, copy-number variation (CNV) analysis and RNA sequencing in CML patients has been performed by Branford et al [96].…”