Mutant IDH1 blocks neutropoiesis by repressing myeloid progenitor programs
Abstract
Abstract IDH1 and IDH2 are frequently mutated in various cancers, including acute leukemias. However, the distinct mechanisms by which mutant IDH1 or IDH2 drive hematopoietic neoplasms remain poorly understood. Here, we analyzed DNA methylation in IDH1- and IDH2-mutant acute myeloid leukemia and found neutrophil lineage-specific epigenetic alterations in IDH1-mutant patients that went along with severely impaired neutrophil differentiation. Transcriptional analysis of normal hematopoiesis in humans and mice revealed a strong physiological upregulation of IDH1/Idh1 in myeloid progenitors. To study the functional effects of Idh1 mutations on hematopoiesis in a preleukemic setting, we used a genetically engineered inducible mouse model expressing a heterozygous Idh1 mutation under control of the endogenous promotor. Our study revealed a cell-intrinsic block in neutrophil differentiation caused by repression of myeloid transcription programs in neutrophil progenitors. This included impaired expression of Cebpe, which encodes a key transcription factor regulating neutrophil differentiation. Reactivation of Cebpe expression, by overexpression of its upstream regulator Cebpa or following treatment with hypomethylating agents, restored differentiation, indicating that the differentiation block is reversible. In summary, we found a reversible, preleukemic impairment of neutrophil differentiation in IDH1-mutant hematopoiesis that correlates with elevated IDH1 expression in myeloid progenitors and likely explains the strong association of IDH1 mutations with myeloid neoplasms.
Article Details
Authors (28)
Mariam Hakobyan
1Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center, Heidelberg, Germany
Jens Langstein
1Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center, Heidelberg, Germany
María José Ramos Medina
1Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center, Heidelberg, Germany
Emely Kleinert
1Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center, Heidelberg, Germany
Maximilian Schönung
1Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center, Heidelberg, Germany
Mark Hartmann
1Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center, Heidelberg, Germany
Hannah Rohdjess
Jessica Wojtarowicz
1Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center, Heidelberg, Germany
Sina Staeble
1Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center, Heidelberg, Germany
Melissa Türe
1Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center, Heidelberg, Germany
Yasmine Pobiedonoscew
1Section of Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center, Heidelberg, Germany
Rainer Claus
From Bielefeld University, Medical School and University Medical Center Ostwestfalen-Lippe, Campus Hospital Lippe, Detmold, Germany (J.H.); the Department of Radiation Oncology, Medical University of Graz, Graz, Austria (T.B.); the Clinical Trials Unit, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany (C.S.); the Institute of Surgical Pathology, University Medical Center Freiburg, Germany (P.B.); the Department of Surgery, University Medical Center Schleswig-Holstein–Campus Lübeck, Lübeck, Germany (B.K., T.K.); Comprehensive Cancer Center Augsburg, Faculty of Medicine, University of Augsburg, Augsburg, Germany (R.C.); the Department of General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany (S.U.); the Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg–Eppendorf, Hamburg, Germany (J.R.I.); the Department of Gastrointestinal Surgery, IRCCS San Raffaele Scientific Institute and San Raffaele Vita-Salute Universi...
Lars Bullinger
Christopher C. Oakes
7Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
Katharina Zoldan
8Department for Hematology, Cell Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany
Michael Cross
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Uwe Platzbecker
Niclas Kneisel
9Servier Germany GmbH, Munich, Germany
Simon Raffel
Ulrich Germing
Gregor Hoermann
12MLL Munich Leukemia Laboratory, Munich, Germany
Simon Haas
Karsten Rippe
Stefan Fröhling
Stefan Pusch
16German Cancer Consortium, Core Center Heidelberg, Heidelberg, Germany
Christoph Plass
Michael D. Milsom
4Division of Experimental Hematology, German Cancer Research Center, Heidelberg, Germany
Daniel B. Lipka