ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells
Copyright policy )ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells
AbstractZBTB7A 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.
Oncogene Proteins, Fusion, Carcinogenesis, Cell Line, Tumor [MeSH] ; Acute myeloid leukaemia ; Glycolysis/drug effects [MeSH] ; Core Binding Factor Alpha 2 Subunit/metabolism [MeSH] ; Transcription Factors/genetics [MeSH] ; Cell Differentiation/drug effects [MeSH] ; Core Binding Factor Alpha 2 Subunit/genetics [MeSH] ; DNA-Binding Proteins/genetics [MeSH] ; Tetradecanoylphorbol Acetate/pharmacology [MeSH] ; DNA-Binding Proteins/metabolism [MeSH] ; Gene Knockout Techniques [MeSH] ; Leukemia, Myeloid, Acute/genetics [MeSH] ; Xenograft Model Antitumor Assays [MeSH] ; Glycolysis/genetics [MeSH] ; Transcription Factors/metabolism [MeSH] ; RUNX1 Translocation Partner 1 Protein/genetics [MeSH] ; Carcinogenesis/drug effects [MeSH] ; Deoxyglucose/therapeutic use [MeSH] ; Humans [MeSH] ; Cell Lineage/genetics [MeSH] ; Hematopoiesis/drug effects [MeSH] ; RUNX1 Translocation Partner 1 Protein/metabolism [MeSH] ; Oncogene Proteins, Fusion/genetics [MeSH] ; Cell Differentiation/genetics [MeSH] ; Animals [MeSH] ; Loss of Function Mutation [MeSH] ; Cell Cycle Checkpoints/genetics [MeSH] ; Hematopoiesis/genetics [MeSH] ; Mice [MeSH] ; Article ; Hematopoietic Stem Cells/pathology [MeSH] ; Cancer genetics ; Myeloid Progenitor Cells/pathology [MeSH] ; Bone Marrow/pathology [MeSH] ; Leukemia, Myeloid, Acute/drug therapy [MeSH] ; Carcinogenesis/genetics [MeSH] ; Oncogene Proteins, Fusion/metabolism [MeSH] ; Cancer metabolism ; Deoxyglucose/pharmacology [MeSH] ; Leukemia, Myeloid, Acute/pathology [MeSH], Deoxyglucose, Article, Gene Knockout Techniques, Mice, Bone Marrow, Loss of Function Mutation, Cell Line, Tumor, Animals, Humans, Cell Lineage, Myeloid Progenitor Cells, Cell Differentiation, Cell Cycle Checkpoints, Hematopoietic Stem Cells, Hematopoiesis, DNA-Binding Proteins, Leukemia, Myeloid, Acute, Core Binding Factor Alpha 2 Subunit, Glycolysis
Oncogene Proteins, Fusion, Carcinogenesis, Cell Line, Tumor [MeSH] ; Acute myeloid leukaemia ; Glycolysis/drug effects [MeSH] ; Core Binding Factor Alpha 2 Subunit/metabolism [MeSH] ; Transcription Factors/genetics [MeSH] ; Cell Differentiation/drug effects [MeSH] ; Core Binding Factor Alpha 2 Subunit/genetics [MeSH] ; DNA-Binding Proteins/genetics [MeSH] ; Tetradecanoylphorbol Acetate/pharmacology [MeSH] ; DNA-Binding Proteins/metabolism [MeSH] ; Gene Knockout Techniques [MeSH] ; Leukemia, Myeloid, Acute/genetics [MeSH] ; Xenograft Model Antitumor Assays [MeSH] ; Glycolysis/genetics [MeSH] ; Transcription Factors/metabolism [MeSH] ; RUNX1 Translocation Partner 1 Protein/genetics [MeSH] ; Carcinogenesis/drug effects [MeSH] ; Deoxyglucose/therapeutic use [MeSH] ; Humans [MeSH] ; Cell Lineage/genetics [MeSH] ; Hematopoiesis/drug effects [MeSH] ; RUNX1 Translocation Partner 1 Protein/metabolism [MeSH] ; Oncogene Proteins, Fusion/genetics [MeSH] ; Cell Differentiation/genetics [MeSH] ; Animals [MeSH] ; Loss of Function Mutation [MeSH] ; Cell Cycle Checkpoints/genetics [MeSH] ; Hematopoiesis/genetics [MeSH] ; Mice [MeSH] ; Article ; Hematopoietic Stem Cells/pathology [MeSH] ; Cancer genetics ; Myeloid Progenitor Cells/pathology [MeSH] ; Bone Marrow/pathology [MeSH] ; Leukemia, Myeloid, Acute/drug therapy [MeSH] ; Carcinogenesis/genetics [MeSH] ; Oncogene Proteins, Fusion/metabolism [MeSH] ; Cancer metabolism ; Deoxyglucose/pharmacology [MeSH] ; Leukemia, Myeloid, Acute/pathology [MeSH], Deoxyglucose, Article, Gene Knockout Techniques, Mice, Bone Marrow, Loss of Function Mutation, Cell Line, Tumor, Animals, Humans, Cell Lineage, Myeloid Progenitor Cells, Cell Differentiation, Cell Cycle Checkpoints, Hematopoietic Stem Cells, Hematopoiesis, DNA-Binding Proteins, Leukemia, Myeloid, Acute, Core Binding Factor Alpha 2 Subunit, Glycolysis
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