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CSF3R T618I collaborates with RUNX1-RUNX1T1 to expand hematopoietic progenitors and sensitizes to GLI-inhibition [single-cell RNA-seq]

ABSTRACT: Activating CSF3R mutations are recurrent in 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, as well as 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232187 | GEO | 2023/10/18

REPOSITORIES: GEO

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

Project description:Activating CSF3R mutations are recurrent in 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, as well as 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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