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. 2013 Sep;27(9):1870-3.
doi: 10.1038/leu.2013.122. Epub 2013 Apr 22.

CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia

A Pardanani  1 , T L Lasho, R R Laborde, M Elliott, C A Hanson, R A Knudson, R P Ketterling, J E Maxson, J W Tyner, A Tefferi
Affiliations

CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia

A Pardanani et al. Leukemia. 2013 Sep.

Abstract

Truncation mutations of the receptor cytoplasmic domain for colony-stimulating factor 3 (CSF3R) are frequently seen in severe congenital neutropenia, whereas activating missense mutations affecting the extracellular domain (exon 14) have been described in hereditary neutrophilia and chronic neutrophilic leukemia (CNL). In order to clarify mutational frequency, specificity and phenotypic associations, we sequenced CSF3R exons 14-17 in 54 clinically suspected cases of CNL (n=35) or atypical chronic myeloid leukemia (aCML; n=19). Central review of these cases confirmed WHO-defined CNL in 12 patients, monoclonal gammopathy (MG)-associated CNL in 5 and WHO-defined aCML in 9. A total of 14 CSF3R mutations were detected in 13 patients, including 10 with CSF3RT618I (exon 14 mutation, sometimes annotated as CSF3R T595I). CSF3RT618I occurred exclusively in WHO-defined CNL with a mutational frequency of 83% (10 of 12 cases). CSF3R mutations were not seen in aCML or MG-associated CNL. CSF3RT618I was also absent among 170 patients with primary myelofibrosis (PMF; n=76) or chronic myelomonocytic leukemia (CMML; n=94). SETBP1 mutational frequencies in WHO-defined CNL, aCML, CMML and PMF were 33, 0, 7 and 3%, respectively. Four CSF3RT618I-mutated cases co-expressed SETBP1 mutations. We conclude that CSF3RT618I is a highly sensitive and specific molecular marker for CNL and should be incorporated into current diagnostic criteria.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Kaplan–Meier survival curves for patients with WHO-defined CNL without MG (n=12), MG-associated CNL (n=6), and unconfirmed CNL (not meeting WHO diagnostic criteria; n=17).
Figure 2
Figure 2
Kaplan–Meier survival curves for patients with clinically suspected CNL who were found to harbor CSF3R mutations (n=13) versus those without CSF3R mutations (n=22).
Figure 3
Figure 3
Kaplan–Meier survival curves for patients with clinically suspected CNL who were found to harbor SETBP1 mutations (n=6) versus those without SETBP1 mutations (n=29).
See this image and copyright information in PMC

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