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Abstract
The inv(16) acute myeloid leukemia-associated CBFβ-MYH11 fusion is proposed to block normal myeloid differentiation, but whether this subtype of leukemia cells is poised for a unique cell lineage remains unclear. Here, we surveyed the functional consequences of CBFβ-MYH11 in primary inv(16) patient blasts, upon expression during hematopoietic differentiation in vitro and upon knockdown in cell lines by multi-omics profiling. Our results reveal that primary inv(16) AML cells share common transcriptomic signatures and epigenetic determiners with megakaryocytes and erythrocytes. Using in vitro differentiation systems, we reveal that CBFβ-MYH11 knockdown interferes with normal megakaryocyte maturation. Two pivotal regulators, GATA2 and KLF1, are identified to complementally occupy RUNX1-binding sites upon fusion protein knockdown, and overexpression of GATA2 partly induces a gene program involved in megakaryocyte-directed differentiation. Together, our findings suggest that in inv(16) leukemia, the CBFβ-MYH11 fusion inhibits primed megakaryopoiesis by attenuating expression of GATA2/KLF1 and interfering with a balanced transcriptional program involving these two factors.
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1 Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Department of Molecular Biology, Faculty of Science, Nijmegen, The Netherlands (GRID:grid.5590.9) (ISNI:0000000122931605)
2 Radboud Institute for Molecular Life Sciences, Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands (GRID:grid.461760.2)
3 Hôpital Necker Enfants-Malades, Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151; and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France (GRID:grid.412134.1) (ISNI:0000 0004 0593 9113)
4 University of Amsterdam, Department of Hematopoiesis, Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262)
5 Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Department of Molecular Biology, Faculty of Science, Nijmegen, The Netherlands (GRID:grid.5590.9) (ISNI:0000000122931605)
6 Hôpital Necker Enfants-Malades, Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151; and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France (GRID:grid.412134.1) (ISNI:0000 0004 0593 9113); University College Dublin, Systems Biology Ireland, School of Medicine, Dublin, Ireland (GRID:grid.7886.1) (ISNI:0000 0001 0768 2743); Our Lady’s Children’s Hospital Crumlin, National Children’s Research Centre, Dublin, Ireland (GRID:grid.417322.1) (ISNI:0000 0004 0516 3853)
7 Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Department of Molecular Biology, Faculty of Science, Nijmegen, The Netherlands (GRID:grid.5590.9) (ISNI:0000000122931605); Università degli Studi della Campania ‘Luigi Vanvitelli’, Dipartimento di Biochimica, Biofisica e Patologia generale, Napoli, Italy (GRID:grid.9841.4) (ISNI:0000 0001 2200 8888)