Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Abstract

Key Points• Recurrent mutations in chromatin modifiers and cohesin were observed in t(8;21) AML, but not inv (16 . Mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML. In contrast, mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies in t(8;21) AML (42% and 18%, respectively), whereas they were nearly absent in inv(16) AML. High KIT mutant allele ratios defined a group of t(8;21) AML patients with poor prognosis, whereas high N/KRAS mutant allele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome. In addition, mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis in patients with tyrosine kinase pathway mutations, suggesting synergic cooperation between these events. These data suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21) vs inv(16) AML.

Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia

“…While some previously reported molecular features of CBF-AML, such as KIT and RAS mutations, are shared by both t(8;21)- and inv(16)-positive CBF-AML, mutations in the cohesin complex and chromatin remodeling genes are more frequently found in AML with t(8;21) than in AML with inv(16). 7,8 The recent discoveries of recurring mutations in ASXL2 9 and ZBTB7A 10,11 that occur either exclusively ( ASXL2 9,11 ) or almost exclusively ( ZBTB7A 10,11 ) in t(8;21)-positive CBF-AML further support the existence of specific mutations that distinguish patients with t(8;21) from those with inv(16).…”

“…A recent comprehensive study of gene mutations in CBF-AML 7 detected the presence of at least one mutation in 85% of the patients studied, thus leaving a possibility that the remaining 15% of patients harbor other, as yet not discovered, mutations. Therefore, we hypothesized that novel, hitherto not reported gene mutations may still exist, and if so, that they might contribute to clinical and molecular differences between CBF-AML patients with t(8;21) and those carrying inv(16).…”

The Role of Additional Sex Combs-Like Proteins in Cancer

“…Interestingly, ASXL1 and ASXL2 mutations are mutually exclusive in t(8;21) AML suggesting that the mutations may have convergent downstream and/or are synthetic lethal effects with one another. A recent targeted mutational analysis of t(8;21) AML suggests that these mutations are also mutually exclusive with mutations in other epigenetic modifiers, such as EZH2 , and when associated with tyrosine kinase mutations are associated with an increased risk of relapse (Duployez et al 2016). In sequencing analysis of t(8;21) AML, a single patient with an ASXL3 mutation has been described but otherwise ASXL3 mutations have been very infrequently reported in hematological malignancies (Duployez et al 2015a).…”

A Review of DNA Methylation and microRNA Expression in Recurrent Pediatric Acute Leukemia

“…Similarly, relapse in AML has been attributed to a subclone of leukemia present at diagnosis, which survives therapy and reemerges due to additional accumulation of mutations, or to a preleukemia clone that survives therapy and acquires additional mutations during remission [13] . Recent genomic and DNA microarray studies have implicated numerous genes and molecular abnormalities in childhood acute leukemia relapse [11,[13][14][15] , suggesting a complex mechanism that unfortunately continues to remain elusive. As current therapeutic strategies for leukemia relapse often result in chemoresistance, advances in biomarkers of relapse and therapeutic regimens are urgently needed.…”