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Redondo Monte, E.* ; Wilding, A.* ; Leubolt, G.* ; Kerbs, P.* ; Bagnoli, J.W.* ; Hartmann, L.* ; Hiddemann, W.* ; Chen-Wichmann, L.* ; Krebs, S.* ; Blum, H.* ; Cusan, M.* ; Vick, B. ; Jeremias, I. ; Enard, W.* ; Theurich, S.* ; Wichmann, C.* ; Greif, P.A.*

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

Oncogene 39, 3195–3205 (2020)
Publ. Version/Full Text DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Aml1-eto; Mutations; Leukemia; Fate; Repression; Lrf
ISSN (print) / ISBN 0950-9232
e-ISSN 0950-9232
Journal Oncogene
Quellenangaben Volume: 39, Issue: , Pages: 3195–3205 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Macmillan Building, 4 Crinan St, London N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)