Phenotypic variability within the JAK2 V617F-positive MPD: Roles of progenitor cell and neutrophil allele burdens

Objective The myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), differ phenotypically, but share the same JAK2V617F mutation. We examined the relationship of the quantitative JAK2V617F allele burden to MPD disease phenotype among the three MPD classes and within PV. Materials and Methods We measured the JAK2V617F allele percentage in genomic DNA from neutrophils, CD34+ cells, and cloned progenitors in 212 JAK2V617F-positive MPD patients and correlated the allele burdens to both disease class and disease features. Results In ET and PV, mean CD34+ cell JAK2V617F allele burdens were lower than the corresponding neutrophil allele burdens, but these were equivalent in PMF. JAK2WT progenitors were present in ET and PV when the CD34+ JAK2V617F allele burden was lower than the neutrophil allele burden, but not in PV and PMF subjects in whom the CD34+ cell and neutrophil allele burdens were similar. CD34+ cell JAK2V617F clonal dominance, defined as coherence between the CD34+ cell and neutrophil JAK2V617F allele burdens, was present in 24% of ET, 56% of PV, and 93% of PMF patients, and was independent of the CD34+ cell JAK2V617F genotype. Clonally dominant PV patients had significantly longer disease durations, higher white cell counts, and larger spleens than nondominant PV patients. Conclusions We conclude that the extent of JAK2V617F CD34+ cell clonal dominance is associated with disease phenotype within the MPD and, in PV, is associated with extramedullary disease, leukocytosis, and disease duration.