Clonal analyses reveal associations of JAK2V617F homozygosity with hematologic features, age and gender in polycythemia vera and essential thrombocythemia

Abstract

Subclones homozygous for JAK2V617F are more common and larger in patients with polycythemia vera compared to essential thrombocythemia, but their role in determining phenotype remains unclear. We genotyped 4564 erythroid colonies from 59 patients with polycythemia vera or essential thrombocythemia to investigate whether the proportion of JAK2V617F -homozygous precursors, compared to heterozygous precursors, is associated with clinical or demographic features. In polycythemia vera, a higher proportion of homozygous-mutant precursors was associated with more extreme blood counts at diagnosis, consistent with a causal role for homozygosity in polycythemia vera pathogenesis. Larger numbers of homozygous-mutant colonies were associated with older age, and with male gender in polycythemia vera but female gender in essential thrombocythemia. These results suggest that age promotes development or expansion of homozygous-mutant clones and that gender modulates the phenotypic consequences of JAK2V617F homozygosity, thus providing a potential explanation for the long-standing observations of a preponderance of men with polycythemia vera but of women with essential thrombocythemia.

Figure 1.

Possible models to explain the associations of JAK2V617F homozygosity with gender in PV and ET. Each symbol represents one patient. Starting from a pool of individuals with subclinical JAK2V617F heterozygous mutations (pink symbols), there are three possible outcomes: acquisition of a significant JAK2V617F-homozygous clone (red symbols); acquisition of other mechanisms that can drive PV (green symbols); or maintenance of JAK2V617F heterozygosity alone. (A) JAK2V617F homozygosity occurs at a higher rate in males compared to females, but the phenotypic consequences of homozygosity are equivalent between males and females: most individuals develop PV and a minority develop ET. Of those individuals who remain JAK2V617F-heterozygous, some develop PV as a consequence of mechanisms other than JAK2V617F homozygosity, and others develop ET. (B) JAK2V617F homozygosity occurs at an equivalent rate in males and females but the phenotypic consequences are different: homozygosity in males is more likely to lead to PV than homozygosity in females, because of other factors that facilitate erythropoiesis in males and/or constrain erythropoiesis in females. The relative numbers of individuals with each genotype are approximations for illustrative purposes, and are not derived directly from the colony analysis.