Journal
CELL STEM CELL
Volume 29, Issue 2, Pages 298-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2021.12.007
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Funding
- NIH [R01CA216421, R01CA173636, R01CA228135, R01CA242020, 1RO1CA266212, 1RO1HL159175, R35HL135787, R01DK102759, R01DK113639, L40HL143713, R01CA190261]
- Edward P. Evans MDS Foundation
- Leukemia and Lymphoma Society
- Uehara Memorial Foundation
- NY State Department of Health IDEA program
- Waksman Foundation of Japan
- Mochida Me-morial Foundation for Medical and Pharmaceutical Research
- Cincinnati Children's Hospital Research Foundation
- Japan Society for the Promotion of Science
- Cancer Free Kids
- Pelotonia Fellowship
- American Society of Hematology and Gilead Sciences
- NY State Department of Health IIRP program
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Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of pre-leukemic cells that acquire specific mutations. TRAF6, a ubiquitin ligase gene, is identified to cooperate with pre-leukemic cells and its loss leads to overt myeloid leukemia through MYC-dependent stem cell signatures. Repression of TRAF6 signaling can potentially contribute to the development of acute leukemia.
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.
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