The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in Mice that is responsive to therapeutic JAK inhibition

Angela G. Fleischman, Julia E. Maxson, Samuel B. Luty, Anupriya Agarwal, Lacey R. Royer, Melissa L. Abel, Jason D. Macmaniman, Marc M. Loriaux, Brian J. Druker, Jeffrey W. Tyner

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

We have recently identified targetable mutations in CSF3R (GCSFR) in 60% of chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL-negative) chronic myeloid leukemia (aCML) patients. Here we demonstrate that the most prevalent, activating mutation, CSF3R T618I, is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model. Mice transplanted with CSF3R T618I-expressing hematopoietic cells developed a myeloproliferative disorder characterized by overproduction of granulocytes and granulocytic infiltration ofthe spleen and liver, which was uniformly fatal. Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood count and reduced spleen weight. This demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. This murine model is an excellent tool for the further study of neutrophilic myeloproliferative neoplasms and implicates the clinical use of JAK inhibitors for this disease.

Original languageEnglish (US)
Pages (from-to)3628-3631
Number of pages4
JournalBlood
Volume122
Issue number22
DOIs
StatePublished - Nov 21 2013

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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