JAK2^{Exon 12} Mutant Allele Burden Study (JETMABS): A European Multicenter Study

A subset of polycythemia vera (PV) patients harbor mutations in a discrete region of exon 12 in the JAK2 gene. So far more than 40 individual mutations have been described involving amino acids 533 to 547 including substitutions, deletions, and duplications. Several studies have indicated that a higher JAK2^V617F mutant allele burden may be associated with a more extreme PV, but both the variability and rarity of the JAK2^{exon 12} mutations have limited the number of studies describing how they reflect disease development and influence thrombotic events. To investigate the impact of the JAK2^{exon 12} mutant allele burden on the disease phenotype and its utility as a prognostic marker, we established a European collaboration termed JAK2^{Exon 12} Mutated Allele Burden Study (JETMABS).

Eighty six samples from 66 individual JAK2^{exon 12} positive PV patients (median age 64 years, range 32-88 years) were collected from participating centers and mutant allele burden was determined by allele specific qPCR evaluating 11 different JAK2^{exon 12} mutations. Depending on the participating center the DNA was either purified from whole blood (n=36; mutated alleles, median 20%, range 1.0-99%) or from granulocytes (n=30; mutated alleles, median 21%, range 8.9-51%). These were divided into separate groups as purification of DNA from granulocytes appeared to result in a slightly higher estimated mutant allele burden, as expected. The vast majority of patients had a mutant allele burden below 50% regardless of the source of DNA (60 out of 64 patients). Both hemoglobin (Hb) (Spearman r=0.41, P<0.05) and hematocrit (Hct) (Spearman r=0.49, P<0.05) levels correlated significantly with the mutant allele burden in the samples purified from granulocytes. The pre-diagnosis thrombotic events did not correlate with the mutant allele burden, but the two cases with the highest mutant allele burdens (88% and 99%) were the only ones to experience thrombotic events post-diagnosis. Four patients developed non-hematological secondary cancers, two patients progressed to post-PV myelofibrosis, and one patient developed AML.

The JAK2^{exon 12} mutant allele burden did not seem to influence the pre-thrombotic events in PV patients. The allele burden only exceeded 50% in a few cases, which was associated with post-thrombotic events. Although this does not seem to reflect the dynamics of the more aggressive JAK2^V617F counterpart, these few patients may require a more intensive treatment strategy.

No relevant conflicts of interest to declare.