Carrying 2 loss-of-function mutations in JAK2 — a state known as nullizygosity — may be associated with decreased survival in primary myelofibrosis (PMF), according to study results published in The American Journal of Hematology.

Previously, researchers at the Mayo Clinic in Rochester, Minnesota, showed an association between decreased survival in PMF and nullizygosity for the JAK2 germline GGCC (46/1) haplotype. In this study, they increased the number of informative cases from 130 to 414 to further assess the link between the JAK2 46/1 haplotype and prognosis and survival in PMF.

In this expanded population of patients with PMF, the median age was 63 years, and 63% were men. Nearly 70% of the patients harbored the JAK2 46/1 haplotype, with 25% homozygous patients and 44% heterozygous patients.

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The frequency of driver mutations in patients homozygous for the 46/1 haplotype was 78% for JAK2, 10% for type 1-like CALR, 3% for type 2-like CALR, 4% for MPL, and 6% for triple negative cases. The frequency of driver mutations in patients heterozygous for the 46/1 haplotype was 60% for JAK2, 20% for type 1-like CALR, 2% for type 2-like CALR, 8% for MPL, and 10% for triple-negative cases. The frequency of driver mutations in patients nullizygous for the 46/1 haplotype was 56% for JAK2, 18% for type 1-like CALR, 5% for type 2-like CALR, 7% for MPL, and 14% for triple-negative cases (P =.02).

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Nullizygosity for the JAK2 46/1 haplotype was correlated with worse overall survival (hazard ratio [HR] 1.5; 95% CI, 1.1-1.9), and the effect was more pronounced in patients with JAK2 driver mutation (P <.001) but not patients with CALR or MPL driver mutations (P =.48) or triple-negative cases (P =.27).

Analyses that included driver mutational status, karyotype, and high-molecular risk mutations indicated that nullizygosity served as an independent prognostic factor for survival in PMF (P =.02; HR 1.4; 95% CI, 1.1-1.8).

The 46/1 haplotype did not correlate with leukemia-free survival (P =.6).


Tefferi A, Lasho TL, Mudireddy M, et al. The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly-annotated patients with primary myelofibrosis [December 5, 2018]. Am J Hematol. doi: 10.1002/ajh.25349