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Granulocyte colony-stimulating factor receptor T595I (T618I) mutation confers ligand independence and enhanced signaling

Leukemia volume 27, pages 2407–2410 (2013)Cite this article

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Although acquired nonsense mutations occurring in the intracellular domain of the granulocyte colony-stimulating factor receptor (GCSFR, gene name CSF3R) occur in patients with severe congenital neutropenia (SCN), these and other missense mutations have rarely been reported in other disorders. Two recent reports have identified CSF3R T595I as a recurrent mutation in patients with chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (aCML). Exon sequencing of patients with CNL or aCML identified the CSF3R T595I mutation occurring exclusively in CNL. CSF3R mutations were not seen in aCML, primary myelofibrosis or chronic myelomonocytic leukemia (CMML), suggesting its strong, specific association with CNL.1 Another study revealed activating mutations of CSF3R in more than half of patients with CNL or aCML, the great majority due to T595I. This also conferred in vitro sensitivity to JAK inhibition, and administration of ruxolitinib to a patient with CNL and CSF3R T595I, which resulted in marked clinical improvement.2 Unlike those children and adolescents with SCN who are treated chronically with pharmacological doses of recombinant human GCSF, these individuals are much older and have no antecedent exposure to GCSF. Interestingly, this same mutation was observed in a patient with SCN who first acquired the classical nonsense mutation at codon 715 of the CSF3R (d715). This patient later developed acute myeloid leukemia (AML) with compound CSF3R mutations (d715+T595I) present in the leukemic blasts.3

We have screened patients with myeloid neoplasms, including sAML (n=37), myelodysplastic syndromes (MDS; n=120) and MDS/myeloproliferative neoplasms (MDS/MPNs; n=48), for the presence of CSF3R mutations using next-generation sequencing. Informed consent has been obtained according to the institutional review board. We also analyzed The Cancer Genome Atlas database of 205 AML cases. We report the detection of the recurrent CSF3R T595I mutation in a 64-year-old man who carried the diagnosis of CMML with normal cytogenetics and negative fluorescent in situ hybridization studies. The patient’s total white blood cell count was 38 290/μl; Hg 10.7 g/dl; hematocrit 32.8; mean corpuscular volume 98.5 fl; red cell distribution width 17.5%; platelet count 198 000/μl; nucleated RBC 60/μl. The peripheral blood differential was 78% neutrophils, 10% bands, 1% metamyelocytes, 6% lymphocytes and 5% monocytes with no blasts or young unidentified forms. His peripheral monocyte count varied with 10–13% monocytosis before therapeutic intervention. Hypogranular neutrophils were seen on the peripheral smear and dysplasia of the erythroid, and megakaryocytic lineages were found in the bone marrow. The bone marrow biopsy showed no fibrosis. There were no mutations in SETBP1, KRAS, NRAS or CBL. In addition to this patient, two patients were identified from The Cancer Genome Atlas with the CSF3R T595I mutation. In a separate large AML study, five patients (out of 1446 de novo AML cases) were found to harbor CSF3R T595I.4 That study also revealed two patients with CSF3R T617N (T630N), a mutation involving the transmembrane domain, which had been previously found in 2 (out of 555) patients with AML5 and in an extended family with hereditary neutrophilia.6

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Author notes

  1. H M Mehta and T Glaubach: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics (Hematology–Oncology) and Cell and Molecular Biology, Lurie Children’s Hospital of Chicago, and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    H M Mehta, T Glaubach, A Long, H Lu & S J Corey

  2. Department of Hematologic Oncology and Blood Disorders, Leukemia Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA

    B Przychodzen, H Makishima & J Maciejewski

  3. Translational Hematology and Oncology Research, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA

    B Przychodzen, H Makishima & J Maciejewski

  4. Departments of Medicine and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    M A McDevitt

  5. Faculty of Medicine, University of Southampton, Southampton, UK

    N C P Cross

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Correspondence to S J Corey.

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NCP cross receives honoraria from Novartis.

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Mehta, H., Glaubach, T., Long, A. et al. Granulocyte colony-stimulating factor receptor T595I (T618I) mutation confers ligand independence and enhanced signaling. Leukemia 27, 2407–2410 (2013). https://doi.org/10.1038/leu.2013.164

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