IDH1 Mutations Can Drive AML through TET2-Independent Mechanisms

Mutations in isocitrate dehydrogenase-1 (IDH1) frequently drive acute myeloid leukemia (AML) tumorigenesis. Mutant IDH1 inhibits TET2, an enzyme involved in cytosine demethylation, resulting in disrupted DNA methylation and differentiation. However, IDH1-mutant disease is clinically distinct from TET2-mutant disease, indicating that IDH1 likely has a TET2-independent role in AML. A previous study in myeloid-specific IDH1-mutant mice revealed global changes in DNA and histone methylation and disruption of hematopoietic stem cell (HSC) differentiation, but the underlying molecular mechanisms are not fully understood. Inoue, Li, Tseng, and colleagues showed that in progenitor cells and HSCs from IDH1-mutant mice, DNA damage response (DDR) signaling was impaired by downregulation of the DNA damage sensor ATM, independent of TET2. This ATM downregulation was also observed in IDH1 mutant AML data from The Cancer Genome Atlas (TCGA). Downregulation of ATM by mutant IDH1 was associated with reduced chromatin accessibility at the ATM promoter, and required methylation of histone H3K9. The reduction in ATM in IDH1-mutant cells resulted in impaired DNA repair, with delayed and reduced disappearance of 53BP1 and γH2AX foci, compared with IDH1–wild-type and TET2-knockout cells. Additionally, the reduced DNA repair capacity was associated with reduced self-renewal in HSCs. IDH1-mutant cells exhibited increased sensitivity to irradiation- or daunorubicin-induced DNA damage, resulting in enhanced apoptosis compared with TET2-knockout cells. In addition to previously known TET-dependent alterations to DNA methylation in HSCs and progenitor cells, these findings identify a TET2-independent role of mutant IDH1 whereby mutant IDH1 promotes the accumulation of DNA damage and impaired HSC self-renewal, which may have implications for treatment of IDH1-mutant AML.

Inoue S, Li WY, Tseng A, Beerman I, Elia AJ, Bendall SC, et al. Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2. Cancer Cell 2016;30:337–48.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.