A truncation mutant of Csf3r cooperates with PML-RARα to induce acute myeloid leukemia in mice

Ghada Kunter, Jill R. Woloszynek, Daniel C. Link

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Severe congenital neutropenia is associated with a marked propensity to develop myelodysplasia or acute myeloid leukemia (AML). Truncation mutations of CSF3R, encoding the granulocyte colony-stimulating factor receptor (G-CSFR), are associated with development of myelodysplasia/AML in severe congenital neutropenia. However, a causal relationship between CSF3R mutations and leukemic transformation has not been established. Herein, we show that truncated G-CSFR cooperates with the PML-RARα oncogene to induce AML in mice. Expression of truncated G-CSFR significantly shortens the latency of AML in a G-CSF-dependent fashion and it is associated with a distinct AML presentation characterized by higher blast counts and more severe myelosuppression. Basal and G-CSF-induced signal transducer and activator of transcription 3, signal transducer and activator of transcription 5, and extracellular signal-regulated kinase 1/2 phosphorylation were highly variable but similar in leukemic blasts expressing wild-type and truncated G-CSFR. These data provide new evidence suggesting a causative role for CSF3R mutations in human AML.

Original languageEnglish
Pages (from-to)1136-1143
Number of pages8
JournalExperimental Hematology
Volume39
Issue number12
DOIs
StatePublished - Dec 2011

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