CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition

Anja S Swoboda; Vanessa C Arfelli; Anna Danese; Roland Windisch; Paul Kerbs; Enric Redondo Monte; Johannes W Bagnoli; Linping Chen-Wichmann; Alessandra Caroleo; Monica Cusan; Stefan Krebs; Helmut Blum; Michael Sterr; Wolfgang Enard; Tobias Herold; Maria Colomé-Tatché; Christian Wichmann; Philipp A Greif

doi:10.1097/HS9.0000000000000958

CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition

Hemasphere. 2023 Oct 11;7(10):e958. doi: 10.1097/HS9.0000000000000958. eCollection 2023 Oct.

Authors

Anja S Swoboda^{1

2

3}, Vanessa C Arfelli^{1

2

3}, Anna Danese^{4

5}, Roland Windisch⁶, Paul Kerbs^{1

2

3}, Enric Redondo Monte^{1

2

3}, Johannes W Bagnoli⁷, Linping Chen-Wichmann⁶, Alessandra Caroleo^{1

2

3}, Monica Cusan^{1

2

3}, Stefan Krebs⁸, Helmut Blum⁸, Michael Sterr^{9

10}, Wolfgang Enard⁷, Tobias Herold^{1

2

3}, Maria Colomé-Tatché^{4

11}, Christian Wichmann⁶, Philipp A Greif^{1

2

3}

Affiliations

¹ Department of Medicine III, University Hospital, LMU Munich, Germany.
² German Cancer Consortium (DKTK), Partner Site Munich, Germany.
³ German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ Computational Health Center, Helmholtz Center Munich, Neuherberg, Germany.
⁵ Department of Physiological Genomics, Biomedical Center Munich, Ludwig-Maximilians University, Germany.
⁶ Division of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Germany.
⁷ Anthropology and Human Genomics, Faculty of Biology, LMU Munich, Martinsried, Germany.
⁸ Gene Center - Laboratory for Functional Genome Analysis, LMU Munich, Germany.
⁹ Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany.
¹⁰ German Center for Diabetes Research (DZD), Neuherberg, Germany.
¹¹ Biomedical Center (BMC), Physiological Chemistry, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany.

Abstract

Activating colony-stimulating factor-3 receptor gene (CSF3R) mutations are recurrent in acute myeloid leukemia (AML) with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of CSF3R and the t(8;21) associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hematopoietic stem and progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, and blast-like morphology and distinct immunophenotype. Gene expression profiling revealed hedgehog signaling as a potential mechanism, with upregulation of GLI2 constituting a putative pharmacological target. Both primary hematopoietic cells and the t(8;21) positive AML cell line SKNO-1 showed increased sensitivity to the GLI inhibitor GANT61 when expressing CSF3R T618I. Our findings suggest that during leukemogenesis, the RUNX1-RUNXT1 fusion and CSF3R mutation act in a synergistic manner to alter hedgehog signaling, which can be exploited therapeutically.