학술논문
CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition
Document Type
article
Author
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
Source
HemaSphere, Vol 7, Iss 10, p e958 (2023)
Subject
Language
English
ISSN
2572-9241
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00000000
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.