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|Ref Type||Journal Article|
|Authors||Fleischman AG, Maxson JE, Luty SB, Agarwal A, Royer LR, Abel ML, MacManiman JD, Loriaux MM, Druker BJ, Tyner JW|
|Title||The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition.|
|Date||2013 Nov 21|
|Abstract Text||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 of the 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.|
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|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
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|CSF3R mutant||bone marrow cancer||not applicable||N/A||Clinical Study||Emerging||In clinical studies, high frequency of CSF3R mutations was identified in patients with chronic neutrophilic leukemia (PMID: 23656643, PMID: 24081659), suggesting that this may serve as a future diagnostic biomarker (PMID: 24441292).||24081659 23656643 24441292|