Department of Medicine III, University Hospital, LMU Munich, 81377, Munich, Germany.
German Cancer Consortium (DKTK), Partner Site Munich, 81377, Munich, Germany.
Oncogene. 2020 Apr;39(15):3195-3205. doi: 10.1038/s41388-020-1209-4. Epub 2020 Mar 2.
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.
ZBTB7A 频繁发生突变，与 t(8;21)易位相关的急性髓系白血病（AML）。然而，AML t(8;21)中突变 ZBTB7A 与 RUNX1-RUNX1T1 融合基因的致癌协同作用尚不清楚。在这里，我们研究了 ZBTB7A 及其突变在正常和恶性造血中的作用。我们证明了 AML t(8;21)中具有临床相关性的 ZBTB7A 突变导致功能丧失，并导致髓系分化失调，粒细胞系受阻，有利于单核细胞分化。此外，ZBTB7A 的缺失增加了糖酵解，从而使白血病细胞对 2-脱氧-D-葡萄糖的代谢抑制更加敏感。我们观察到，野生型 ZBTB7A 的异位表达可阻止 RUNX1-RUNX1T1 介导的人 CD34+细胞的克隆扩增，而 ZBTB7A 突变则使祖细胞的生长得以实现。最后，t(8;21)细胞中的 ZBTB7A 表达导致细胞周期停滞，而糖酵解抑制可模拟这种停滞。我们的研究结果表明，ZBTB7A 的缺失可能促进了 AML t(8;21)的发生，而 RUNX1-RUNX1T1 重排的白血病可能可以用糖酵解抑制剂治疗。
