ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells

Enric Redondo Monte,Paul Kerbs,Linping Chen-Wichmann,Wolfgang Enard,Anja Wilding,Georg Leubolt,Luise Hartmann,Monica Cusan,Stefan Krebs,Philipp A Greif,Binje Vick,Wolfgang Hiddemann,Christian Wichmann,Sebastian Theurich,Johannes W Bagnoli,Helmut Blum,Irmela Jeremias

doi:10.1038/s41388-020-1209-4

Abstract

ZBTB7A is frequently mutated in acute myeloid leukemia (AML) with t(8;21) translocation. However, the oncogenic collaboration between mutated ZBTB7A and the RUNX1–RUNX1T1 fusion gene in AML t(8;21) remains unclear. Here, we investigate the role of ZBTB7A and its mutations in the context of normal and malignant hematopoiesis. We demonstrate that clinically relevant ZBTB7A mutations in AML t(8;21) lead to loss of function and result in perturbed myeloid differentiation with block of the granulocytic lineage in favor of monocytic commitment. In addition, loss of ZBTB7A increases glycolysis and hence sensitizes leukemic blasts to metabolic inhibition with 2-deoxy-d-glucose. We observed that ectopic expression of wild-type ZBTB7A prevents RUNX1-RUNX1T1-mediated clonal expansion of human CD34+ cells, whereas the outgrowth of progenitors is enabled by ZBTB7A mutation. Finally, ZBTB7A expression in t(8;21) cells lead to a cell cycle arrest that could be mimicked by inhibition of glycolysis. Our findings suggest that loss of ZBTB7A may facilitate the onset of AML t(8;21), and that RUNX1-RUNX1T1-rearranged leukemia might be treated with glycolytic inhibitors.

Highlights

We and others found the transcription factor ZBTB7A mutated in acute myeloid leukemia (AML) with translocation t(8;21), at frequencies ranging from 9.4 to 23% [1,2,3,4,5,6]
ZBTB7A function in glycolysis regulation has so far not been studied extensively in the hematopoietic system, but the observed upregulation of glycolytic genes upon ZBTB7A mutation in our patient cohort [1] may counteract the growth arrest caused by RUNX1–RUNX1T1 in AML t(8;21)
We investigate the effect of ZBTB7A mutation on cellular differentiation, glycolysis regulation, and RUNX1–RUNX1T1 directed cell expansion

Summary

Introduction

We and others found the transcription factor ZBTB7A mutated in acute myeloid leukemia (AML) with translocation t(8;21), at frequencies ranging from 9.4 to 23% [1,2,3,4,5,6]. While the RUNX1–RUNX1T1 fusion gene, which results from the t(8;21) translocation, has been studied extensively, it remains unclear how it may provide a fertile ground for the acquisition of genetic lesions in ZBTB7A This oncogenic collaboration may arise from a complementary action on perturbed hematopoietic development (i.e., block of specific arms of the myeloid lineage). While expression of RUNX1–RUNX1T1 in stem cells causes increased proliferation [13], expression in myeloid cell lines results in growth arrest This growth arrest is related to downregulation of MYC [14] and PKM2 [15]—a master regulator of glycolysis and a key enzyme of the glycolytic pathway, respectively. ZBTB7A function in glycolysis regulation has so far not been studied extensively in the hematopoietic system, but the observed upregulation of glycolytic genes upon ZBTB7A mutation in our patient cohort [1] may counteract the growth arrest caused by RUNX1–RUNX1T1 in AML t(8;21). We investigate the effect of ZBTB7A mutation on cellular differentiation, glycolysis regulation, and RUNX1–RUNX1T1 directed cell expansion

Results

Discussion

Methods

Compliance with ethical standards