MYC and TFEB Control DNA Methylation and Differentiation in AML.

Although the MYC transcription factor has been consistently implicated in acute myeloid leukemia (AML), its gene targets and precise role in leukemogenesis remain unknown. In this issue of Blood Cancer Discovery, Yun and colleagues provide evidence that MYC directly suppresses the expression of TFEB, an mTORC1-regulated transcription factor. They show that, in the context of the myelocytic/granulocytic lineage, TFEB acts as a tumor suppressor by inducing the IDH1/2-TET pathway, which in turn, leads to altered DNA methylation and increased expression of genes involved in myeloid differentiation and apoptosis. Therefore, high levels of MYC suppress an epigenetic pathway that should normally act to attenuate leukemic progression. Identification of the components of this pathway is likely to inform new therapeutic tactics for AML and possibly other cancers. See related article by Yun et al., p. 162. ©2021 American Association for Cancer Research.