What Drives Leukemic Transformation of Polycythemia Vera, Essential Thrombocythemia?

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New findings from a small study are suggesting that time to leukemic transformation may be driven by distinct time-dependent molecular mechanisms.

While polycythemia vera (PV) and essential thrombocythemia (ET) are the most indolent myeloproliferative neoplasms (MPNs), their prognosis is dependent on 2 possible complications, one of which is leukemic transformation. New findings from a small study are suggesting that time to this transformation may be driven by distinct time-dependent molecular mechanisms.

Using next-generation sequencing for molecular evaluation of 49 patients with leukemic transformation, as well as pairing samples with diagnosis or chronic phase when available, the researchers of the study determined 3 different molecular groups associated with a different time to leukemic transformation, which took into account the presence or absence of mutations, as well as the allele burden.

“Patients with short-term transformation exhibited a complex molecular landscape with a median of 7 additional mutations. In this group, mutations occurred more specifically in RUNX1, IDH1/2, U2AF1, and TET2 genes,” wrote the researchers, who explained that part of these mutations were present since diagnosis. “On the other hand, patients with a long-term transformation presented, on the contrary, a less complex molecular landscape with preferential mutations in the TP53 and NRAS genes.”


According to the researchers the mutations present in patients with intermediate and long-term transformation could have been present since diagnosis at low levels, or they could appear during leukemic transformation. Notably, these mutations were not detectable even a few months before leukemic transformation in certain cases.

Among the patients, TP53 was the most commonly mutated gene upon leukemic transformation with close with half (45%) of patients having the mutation. The researchers highlighted that this prevalence is higher than that reported in previous research, which has indicated a prevalence rate between 16% to 34%. However, they noted that this could be because their current study did not also include patients with primary myelofibrosis.

No patients with short-term transformation harbored a TP53 mutations. Although half of these mutations were already present at diagnosis/chronic phase, they were present at low levels.

According to the researchers, “The association between TP53 mutations and long-term transformation could be related to the necessary inactivation of the second allele of TP53 for leukemic transformation. Indeed, we found an allele burden higher than 50% or a second mutation in most of the leukemic transformations with the TP53 mutation.”

Meanwhile, there were no mutations of IDH1/2, EZH2, U2AF1, and TET2 in patients with long-term transformation. Overall, there were a total of 191 additional mutations, with a median number of 4 additional mutations and all patients having at least 1 additional mutation.

Having at least 1 additional mutation during the chronic phase was associated with a higher risk of leukemic transformation, according to evaluation of a control groups of patients with stable disease.


Paz D, Jouanneau-Courville R, Riou J, et al. Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation. Blood Adv. Published online October 9, 2020. doi:10.1182/bloodadvances.2020002271