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The CSF3R T618I mutation as a disease-specific marker of atypical CML post allo-SCT

Bone Marrow Transplantation volume 49, pages 843–844 (2014)Cite this article

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Atypical CML (aCML) is a rare myelodysplastic/myeloproliferative neoplasm (MDS/MPN) characterized by neutrophilia with left-shift maturation and dysgranulopoietic features. Diagnosis also requires the exclusion of BCR-ABL1, PDGFRA and PDFRB rearrangements.1 The prognosis of aCML is poor with survival times of generally <30 months: patients may undergo transformation to AML or succumb to the effects of BM failure.2 To date, allo-SCT in the chronic phase of the disease has been the only option to improve OS.3

No specific, recurrent cytogenetic or molecular abnormalities have been described in aCML until the recent characterization of mutations within the genes encoding the G-CSF receptor (CSF3R) and SET binding protein 1 (SETBP1) in a significant proportion of patients with aCML and chronic neutrophilic leukaemia (CNL).4,5 Whereas the functional significance of SETBP1 mutations in aCML and CNL are not yet fully understood, the characterization of CSF3R mutations has revealed a possibility for targeted therapeutic intervention with tyrosine kinase inhibitors. Approximately 50–60% of CNL and aCML patients harbour an acquired CSF3R mutation that can be either membrane proximal or in the cytoplasmic tail of the receptor. These two classes of mutations exhibit different downstream signalling patterns: membrane proximal mutations activate the JAK/STAT pathway and are therefore potentially amenable to inhibition with JAK inhibitors such as ruxolitinib, whereas truncation mutations predominantly signal through SRC family kinases and therefore may be targeted by SRC inhibitors such as dasatinib. The most prevalent CSF3R mutation in aCML and CNL is the membrane proximal T618I.4,6 In addition to this potential for targeted therapy, identification of aCML-specific CSF3R mutations affords the opportunity for evaluation of these mutations as disease-specific markers of residual disease in those patients undergoing allo-SCT. Mutations of SETBP1 and CSF3R exons 14 and 17 were sought by Sanger sequencing in a retrospective series of eight patients with aCML, CNL or atypical MPN. The clinical courses of two aCML patients are described, both of whom possessed a heterozygous CSF3R p.Thr618Ile (T618I) mutation (c.15482C>T, reference sequence NG_016270.1).

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Authors and Affiliations

  1. Cancer Molecular Diagnostics, St James’s Hospital, Dublin 8, Ireland

    S E Langabeer, S L McCarron & K Haslam

  2. Department of Haematology, St James’s Hospital, Dublin 8, Ireland

    M T O'Donovan & E Conneally

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  1. S E Langabeer
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  2. S L McCarron
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  3. K Haslam
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Correspondence to S E Langabeer.

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Langabeer, S., McCarron, S., Haslam, K. et al. The CSF3R T618I mutation as a disease-specific marker of atypical CML post allo-SCT. Bone Marrow Transplant 49, 843–844 (2014). https://doi.org/10.1038/bmt.2014.35

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