ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation

Abstract

The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion.

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 …”

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).…”

GATA2 mutations in myeloid malignancies: Two zinc fingers in many pies

“…The discrepancies between the aforementioned studies may arise from confounders such as the higher prevalence of GATA2 mutation in females, patient age and the favorable prognostic of CEBPA double mutations . Beyond AML with biallelic CEBPA mutations, we and others recently found GATA2 mutations in t(8;21) AML . In fact, AML1‐ETO represses CEBPA transcription, indicating that GATA2 mutations arise on the fertile ground of CEBPA deficiency—due to either CEBPA mutation or downregulation (Figure , right panel).…”

“…9 Beyond AML with biallelic CEBPA mutations, we and others recently found GATA2 mutations in t(8;21) AML. [32][33][34] In fact, AML1-ETO represses CEBPA transcription, 35 indicating that GATA2 mutations arise on the fertile ground of CEBPA deficiency-due to either CEBPA mutation or downregulation (Figure 2, right panel). Another example for this correlation is AML with 3(q21;q26) aberrations, 21 where the overexpression of EVI1 (MECOM) represses CEBPA, 36 thus providing the basis for acquisition of GATA2 mutations.…”