The JAK2 46/1 haplotype does not predispose to CALR -mutated myeloproliferative neoplasms

Somatic mutations in the CALR gene were recently discovered in a substantial proportion of Philadelphia-negative chronic myeloproliferative neoplasm (cMPN) patients lacking JAK2 and MPL mutations. Somatically acquired defects are not the only pathogenic mechanism involved in these disorders. Since germline JAK2 46/1 haplotype predisposes to cMPN-associated mutations, including JAK2 V617F and MPL W515K7L, we evaluated whether the 46/1 haplotype also confers susceptibility to CALR -mutated cMPN, both in sporadic and familial cases. The single-nucleotide polymorphism rs10974944, which tags 46/1, was investigated in 155 sporadic MPN patients and 270 unrelated controls, as well as in 11 familial cMPN cases and 36 unaffected relative controls. As described elsewhere, the 46/1 haplotype was overrepresented, both in sporadic and familial cMPN. In sporadic cMPN, the JAK2 46/1 haplotype was closely associated with JAK2 V617F ( p = 0.0003) but not with JAK2 -nonmutated cases. Analysis of CALR -mutated sporadic cMPN ( n = 22) showed no association between CALR mutations and 46/1 haplotype ( p = 0.87). Regarding the familial cMPN, the prevalence of carriers of the G allele was higher in familial (81.8 %) than in sporadic (62 %) cMPN, but it did not differ significantly ( p = 0.3). Although we described a family with carriers of both JAK2 V617F and CALR mutations, due to the low number of CALR -mutated familial cases, we could not determinate whether the JAK2 46/1 haplotype predisposes or does not to CALR -mutated familial cMPN. We conclude, for the first time, that the 46/1 haplotype, unlike JAK2 V617F and MPL W515K7L, is not associated with CALR -mutated cMPN.