PuSH - Publication Server of Helmholtz Zentrum München: CSF3R T618I collaborates With RUNX1-RUNX1T1 to expand hematopoietic progenitors and sensitizes to GLI inhibition.

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Swoboda, A.S.* ; Arfelli, V.C.* ; Danese, A. ; Windisch, R.* ; Kerbs, P.* ; Redondo Monte, E.* ; Bagnoli, J.W.* ; Chen-Wichmann, L.* ; Caroleo, A.* ; Cusan, M.* ; Krebs, S.* ; Blum, H.* ; Sterr, M. ; Enard, W.* ; Herold, T.* ; Colomé-Tatché, M. ; Wichmann, C.* ; Greif, P.A.*

CSF3R T618I collaborates With RUNX1-RUNX1T1 to expand hematopoietic progenitors and sensitizes to GLI inhibition.

Hemasphere 7:e958 (2023)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Acute Myeloid-leukemia; Self-renewal; Aml1-eto; Mutations; Expression; Dasatinib; Cells; Kinase; Cebpa; Jak2

ISSN (print) / ISBN 2572-9241

e-ISSN 2572-9241

Journal Hemasphere

Quellenangaben Volume: 7, Issue: 10, Article Number: e958

Publisher Wolters Kluwer Health

Publishing Place Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)
Institute of Diabetes and Regeneration Research (IDR)

Grants German Research Foundation (DFG)
"Initiative and Networking Fund" of the Helmholtz Association
Munich Clinician Scientist Program (MCSP) Advanced Track
Wilhelm Sander-Stiftung (Forderantrag)
German Research Foundation (DFG) within the Collaborative Research Centre (SFB) 1243 "Cancer Evolution"