TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity

Cell Stem Cell. 2022 Feb 3;29(2):298-314.e9. doi: 10.1016/j.stem.2021.12.007. Epub 2022 Jan 18.


Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of pre-leukemic cells that acquire specific mutations. Although individuals with CH are healthy, they are at an increased risk of developing myeloid malignancies, suggesting that additional alterations are needed for the transition from a pre-leukemia stage to frank leukemia. To identify signaling states that cooperate with pre-leukemic cells, we used an in vivo RNAi screening approach. One of the most prominent genes identified was the ubiquitin ligase TRAF6. Loss of TRAF6 in pre-leukemic cells results in overt myeloid leukemia and is associated with MYC-dependent stem cell signatures. TRAF6 is repressed in a subset of patients with myeloid malignancies, suggesting that subversion of TRAF6 signaling can lead to acute leukemia. Mechanistically, TRAF6 ubiquitinates MYC, an event that does not affect its protein stability but rather represses its functional activity by antagonizing an acetylation modification.

Keywords: AML; MDS; MPN; MYC; TRAF6; clonal hematopoiesis; hematopoiesis; inflammation; innate immune signaling; myeloid malignancies; ubiquitination.

MeSH terms

  • Hematopoiesis
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Leukemia, Myeloid, Acute* / pathology
  • Mutation
  • Myeloproliferative Disorders*
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism


  • Intracellular Signaling Peptides and Proteins
  • TNF Receptor-Associated Factor 6
  • Tifab protein, human