CALR mutation studies in chronic neutrophilic leukemia

CALR mutation studies in chronic neutrophilic leukemiaTo the Editor: Somatic mutations in calreticulin (CALR), a gene which has not previously been shown to be oncogenic, has recently been identified in BCR-ABL1-negative myeloproliferative neoplasms (MPN) [1,2].These mutations were mutually exclusive of JAK2 and MPL mutations and their frequencies in strictly World Health Organization (WHO)defined disease were 49 and 74% in JAK2/MPL-unmutated ET and PMF, respectively [3,4].CALR mutations have infrequently been reported in other myeloid malignancies including refractory anemia with ring sideroblasts and marked thrombocytosis (13% of 24 patients), myelodysplastic syndromes (8.3% of 120 patients), chronic myelomonocytic leukemia (3% of 33 patients), and atypical chronic myelomonocytic leukemia (3.4% of 29 patients) [1,2].Considering the fact that chronic neutrophilic leukemia (CNL) is morphologically akin to other MPN, it is important to examine its potential association with CALR mutations.We performed CALR mutation analysis in 26 cases of clinically suspected CNL, including eight patients whose diagnosis was confirmed by strict WHO criteria [5].All (100%) of the eight WHO-defined CNL cases carried a CSF3R mutation, including six patients with CSF3RT618I [5].Three of the latter six patients also expressed SETBP1 mutations.Bone marrow-derived DNA was used for CALR mutation screening using previously published methods [4].Our results revealed a novel CALR nucleotide variant (CALRE398D c.1194 G>T) in one case of CNL who was also harboring CSF3RT618I and SETBP1G870D (Fig. 1), resulting in the amino acid substitution of glutamic acid with aspartic acid at amino acid position 398.All CALR mutations currently described in MPN affect exon 9 and were somatic insertions or deletions that resulted in a 11 base pair frame shift, and generation of an altered C-terminal.CALR exon 9 point mutations have rarely been reported in lymphoma (CALRE405Q and CALRE403X) [6] and PMF (CALRE379D) [1].The consequences of an amino acid substitution is not yet known, but the identification of mutations that do not result in generation of a unique C-terminus is suggestive of a different pathogenetic mechanism.