RNA-sequencing analysis of core binding factor AML identifies recurrent ZBTB7A mutations and defines RUNX1-CBFA2T3 fusion signature

Abstract

RUNX1 (also known as AML1 or CBFA2) and CBFB encode the a and b subunits of a heterodimeric core binding transcription factor complex involved in the development of normal hematopoiesis (reviewed by de Bruijn and Speck 1 ). Both genes are rearranged in acute myeloid leukemia (AML) with t(8;21)(q22;q22);RUNX1-RUNX1T1 and inv(16) (p13.1q22)/t(16;16)(p13.1;q22);CBFB-MYH11, which are collectively called core binding factor (CBF) AML. Targeted mutational studies have shown that both CBF AML subgroups are characterized by recurrent mutations in KIT, FLT3, NRAS, and KRAS.2-5 Additional mutations in ASXL2 and ASXL1 were also recently described in t(8;21) AML. 6,7 Mutation analyses employing untargeted approaches in large CBF AML cohorts are still lacking. We previously described comparative transcriptomic approaches leading to the comprehensive description of the mutational and transcriptomic landscape of MLL, 8 EVI1, 9 and NUP98-NSD1 10 AML subgroups. Using this same methodology and cohort, we now report the results of the 48 CBF AML specimens included in our collection of 415 specimens. We identified novel mutations and differentially expressed genes and demonstrated that the RUNX1-CBFA2T3

The genomic landscape of core-binding factor acute myeloid leukemias

“…We also identified recurrent mutations in ZBTB7A /Pokemon (Supplemental Figure 18). The putative loss-of-function mutations identified here are consistent with recent reports of ZBTB7A acting as a tumor suppressor in RUNX1-RUNX1T1 AML 22,60 …”

Beyond KIT in CBF-AML: chromatin and cohesin

“…Strikingly, mutations of chromatin modifiers occurred in 42% of patients with t(8;21), yet were rare in those with inv(16). Additionally, the authors identified recurrent mutations of members of the cohesin complex in 18% of t(8;21) patients and none of the inv(16) patients, consistent with other small recent studies 6,7 (see figure panel A).…”

Regulation of hematopoietic development by ZBTB transcription factors

“…Ivey et al reported 3 cases with LRF mutations out of 223 NPM1 -mutated AML cases (1.3 %) [178]. Furthermore, LRF frameshift mutations, which generate a truncated LRF protein, were recently reported in 3 of 20 cases of AML exhibiting t(8;21) (q22;q22); RUNX1 - RUNX1T1 [179]. It remains unclear whether and how these mutations contribute to leukemogenesis.…”