Distinct Clinical Phenotypes Associated with JAK2V617F Reflect Differential STAT1 Signaling

SummaryThe JAK2V617F mutation is associated with distinct myeloproliferative neoplasms, including polycythemia vera (PV) and essential thrombocythemia (ET), but it remains unclear how it generates disparate disorders. By comparing clonally-derived mutant and wild-type cells from individual patients, we demonstrate that the transcriptional consequences of JAK2V617F are subtle, and that JAK2V617F-heterozygous erythroid cells from ET and PV patients exhibit differential interferon signaling and STAT1 phosphorylation. Increased STAT1 activity in normal CD34-positive progenitors produces an ET-like phenotype, whereas downregulation of STAT1 activity in JAK2V617F-heterozygous ET progenitors produces a PV-like phenotype. Our results illustrate the power of clonal analysis, indicate that the consequences of JAK2V617F reflect a balance between STAT5 and STAT1 activation and are relevant for other neoplasms associated with signaling pathway mutations.

► Effect of JAK2V617F on transcriptome is subtle and less than interindividual variation
► STAT1 is activated in JAK2V617F-heterozygous erythroblasts in ET and not PV
► STAT1 activity provides molecular mechanism for difference between ET and PV
► Power of comparing clonally-derived mutant and wild-type cells from same patient