Editors' ChoiceCancer

Loss of TET2 boosts cell fitness

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Science Translational Medicine  22 Jul 2020:
Vol. 12, Issue 553, eabd3619
DOI: 10.1126/scitranslmed.abd3619

Abstract

The loss of TET2 favors a pathogenic switch to a stem cell–like state in cancer.

For over a decade, mutations in DNA demethylase tet methylcytosine dioxygenase 2 (TET2) have been associated with a variety of myeloid malignancies including de novo acute myeloid leukemia (AML), promoting an unfavorable prognosis. Loss-of-function genetic mutations of TET2 and other genes develop with age in hematopoietic stem cells of individuals without hematological malignancies. The clonal expansion of genetically mutated immune cells in otherwise healthy subjects is referred to as clonal hematopoiesis of indeterminate potential (CHIP) and confers a markedly increased risk of all-cause mortality and cardiovascular death from stroke or myocardial infarction. TET2null myeloid cells are proinflammatory and accelerate atherosclerosis in mice. Major knowledge gaps remain, particularly in understanding how TET2 mutations affect basic cell-state dynamics that contribute to disease states.

Morinishi et al. used an integrated approach of mathematical modeling and experimental validation in wild-type and TET2-knockout (KO) isogenic human AML cell lines to study the effect of TET2 loss on cell fitness, cell proliferation, and drug sensitivity. They showed that loss of TET2 promotes a switch to a stem cell–like state with reduced expression of myeloid differentiation markers associated with transcriptomic and epigenetic changes. Mathematical modeling predicted a functional benefit of the mutant population due to this stem cell–like switch. Experimentally, the authors treated TET2-KO and wild-type cell populations with cytosine arabinoside, a common first-line chemotherapy drug for AML. They found that the TET2-KO mutant cells had a higher rate of switching to a stem cell–like state, which was associated with increased cell survival in the presence of chemotherapy and higher potential for population renewal of the surviving cells.

This proof-of-concept study offers insights into how TET2 loss-of-function mutations may contribute to AML and adverse prognoses. This approach could be leveraged to study the specific effects of individual mutations of TET2 and other genes in cancer. Moreover, validation of these results in relevant model systems could establish mechanistic links between CHIP mutations and atherosclerotic cardiovascular disease and may even offer potential therapeutic opportunities to reduce the cardiovascular risk in the aging population.

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