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Myelodysplasias

Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition

Abstract

Granulocyte colony-stimulating factor (GCSF) drives the production of myeloid progenitor and precursor cells toward neutrophils via the GCSF receptor (GCSFR, gene name CSF3R). Children with severe congenital neutropenia chronically receive pharmacologic doses of GCSF, and 30% will develop myelodysplasia/acute myeloid leukemia (AML) associated with GCSFR truncation mutations. In addition to mutations, multiple isoforms of CSF3R have also been reported. We found elevated expression of the alternatively spliced isoform, class IV CSF3R in adult myelodysplastic syndrome/AML patients. Aside from its association with monosomy 7 and higher rates of relapse in pediatric AML patients, little is known about the biology of the class IV isoform. We found developmental regulation of CSF3R isoforms with the class IV expression more representative of a progenitor cell stage. Striking differences were found in phosphoprotein signaling involving Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and cell cycle gene expression. Enhanced proliferation by class IV GCSFR was associated with diminished STAT3 and STAT5 activation, yet showed sensitivity to JAK2 inhibitors. Alterations in the C-terminal domain of the GCSFR result in leukemic properties of enhanced growth, impaired differentiation and resistance to apoptosis, suggesting that they can behave as oncogenic drivers, sensitive to JAK2 inhibition.

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Acknowledgements

We thank Dr Shigekazu Nagata for providing the cDNA for rabbit GHR and Dr John Crispino for providing the JAK2 inhibitors. Funding to SJC from NIH Independent Scientist Award KO2-HL03794, RO1-CA108992, JP McCarthy Foundation, NIH PO1CA55164, Leukemia SPORE CA100632 and AA/MDS International Foundation; to MF from a New Investigator Award from the AA/MDS International Foundation; and to TG and JRA from NIH T32CA079447.

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Correspondence to S J Corey.

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Mehta, H., Futami, M., Glaubach, T. et al. Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition. Leukemia 28, 1041–1051 (2014). https://doi.org/10.1038/leu.2013.321

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