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Order of JAK2, TET2 mutations influences clinical features of myeloproliferative neoplasms
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The order in which patients with myeloproliferative neoplasms acquired JAK2 and TET2 mutations appeared associated with their clinical features, likelihood of response to targeted therapy and clonal evolution, according to study results.
“This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy,” researcher Anthony R. Green, FRCPath, FMedSci, of the Cambridge Institute for Medical Research, said in a press release. “These results show how study of the myeloproliferative neoplasms provides unparalleled access to the earliest stages of tumor development — [information that is] inaccessible in other cancers, which usually cannot be detected until many mutations have accumulated. This should give us powerful insights into the origins of cancer.”
Green and colleagues sought to identify patients with myeloproliferative neoplasms who had both JAK2 and TET2 mutations in order to evaluate the order of acquisition. Researchers evaluated 246 patients with a JAK2 V617F mutation and, through genetic sequencing, identified 24 patients who also harbored TET2 mutations. Mutation order was established by identifying single-mutant red cell colonies (either JAK2 alone or TET2 alone) in individual patients.
Patients who first presented with TET2 mutations were an average of 12.3 years older than patients who first presented with JAK2 mutations (mean age at diagnosis, 71.5 years vs. 59.2 years; P = .004).
JAK2-first patients had a significantly greater proportion of JAK2 V617F-homozygous colonies of erythroid burst-forming units (P ˂ .001) and megakaryocyte and erythrocyte progenitors (P ˂ .001). However, TET2-first patients were more likely to have common myeloid progenitors than other progenitors in the CD34-positive and CD38-positive compartment (P = .001).
Analyses of 10-day cultures also demonstrated JAK2 V617F reduced progenitor formation when acquired after a TET2 mutation (P = .002), but TET2 mutations increased progenitor expansion when acquired after JAK2 V617F (P = .01). This indicated that individual stem and progenitor cells with the same two genetic mutations were functionally different depending on the order of mutation acquisition, researchers said.
Researchers then evaluated data from an additional 24 patients with both TET2 and JAK2 mutations. In the total cohort (n = 48), JAK2-first patients were younger (mean age at diagnosis, 60.71 years vs. 71.17 years; P = .002), were more likely to have polycythemia vera (P = .05) and were more likely to experience a thrombotic event (P = .002).
In vitro analyses indicated Jakafi (ruxolitinib, Incyte) reduced single-mutant and double-mutant colonies in JAK2-first patients, whereas single-mutant and double-mutant colonies were unchanged in TET2-first patients.
“This surprising finding could help us offer more accurate prognoses to myeloproliferative neoplasm patients based on their mutation order and tailor potential therapies toward them,” researcher David G. Kent, PhD, of the Cambridge Institute for Medical Research and Wellcome Trust/MRC Stem Cell Institute, said in the release. “For example, our results predict that targeted JAK2 therapy would be more effective in patients with one mutation order but not the other.”
Disclosure: Green reports personal fees from Novartis outside the submitted work. Kent reports no relevant financial disclosures. See the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Michael J. Mauro, MD
Ortmann and colleagues have published an eloquent paper on mutation order, specifically focusing on the effects of the now well-known “driver” mutation JAK2, ubiquitous in myeloproliferative neoplasms, and TET2, observed in both myeloid and lymphoid neoplasms as well as accumulating with age in healthy persons with clonal hematopoiesis. With careful study of sole and dual mutated clones, they demonstrate that the order of such mutations has both unique effects on the rate and preferential expansion of clonal hematopoiesis, as well as disease manifestation. One might ascribe a “James Dean” effect to clones with initial JAK2 acquisition, as this led to more erythroid proliferation and clinical polycythemia and manifestation in younger patients with both greater thrombotic risk and sensitivity to ruxolitinib. TET2 “first” was associated with perhaps a more conservative effect seen in older patients, with expansion of common myeloid progenitors and less thrombotic risk. Such granularity in our understanding of molecular defects in hematopoiesis and aging, their order and effect on acquisition of myeloproliferative neoplasms may allow us to harness the right therapeutics to halt transforming crashes as clones speed into the sunset.
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