The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly-annotated patients with primary myelofibrosis

Ayalew Tefferi, Terra L. Lasho, Mythri Mudireddy, Christy M. Finke, Curtis A. Hanson, Rhett P. Ketterling, Naseema Gangat, Animesh Pardanani

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


JAK2 mutations in myeloproliferative neoplasms (MPNs) are associated with the germline GGCC (46/1) haplotype. In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype. In the current study, we have increased the number of informative cases from 130 to 414 (median age 63 years; 63% males), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2, 10%/20%/18% type 1-like CALR, 3%/2%/5% type 2-like CALR, 4%/8%/7% MPL, and 6%/10%/14% triple-negative (P =.02). In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1-1.9), most pronounced in JAK2 (P <.001), as opposed to CALR/MPL mutated (P =.48) or triple-negative cases (P =.27). Multivariable analysis that included karyotype, driver mutational status and high-molecular risk mutations confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype (P =.02; HR 1.4, 95% CI 1.1-1.8). Nullizygosity for 46/1 also remained significant in the context of the genetically-inspired GIPSS risk model (P =.04), but not in the context of the integrated genetics-clinical MIPSS70+ version 2.0 model (P =.4). Leukemia-free survival was not affected by the 46/1 haplotype (P =.6). The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in JAK2-mutated PMF.

Original languageEnglish (US)
Pages (from-to)299-305
Number of pages7
JournalAmerican journal of hematology
Issue number3
StatePublished - Mar 2019

ASJC Scopus subject areas

  • Hematology


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