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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)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Acute Myeloid-leukemia; Self-renewal; Aml1-eto; Mutations; Expression; Dasatinib; Cells; Kinase; Cebpa; Jak2
ISSN (print) / ISBN 2572-9241
e-ISSN 2572-9241
Zeitschrift Hemasphere
Quellenangaben Band: 7, Heft: 10, Seiten: , Artikelnummer: e958 Supplement: ,
Verlag Wolters Kluwer Health
Verlagsort Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)
Institute of Diabetes and Regeneration Research (IDR)
Förderungen 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"