@article{5f68f6d57f16443b944201a13385d9a4,
title = "TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity",
abstract = "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",
author = "Tomoya Muto and Maria Guillamot and Jennifer Yeung and Jing Fang and Joshua Bennett and Bettina Nadorp and Audrey Lasry and Redondo, {Luna Zea} and Kwangmin Choi and Yixiao Gong and Walker, {Callum S.} and Kathleen Hueneman and Bolanos, {Lyndsey C.} and Laura Barreyro and Lee, {Lynn H.} and Greis, {Kenneth D.} and Nikita Vasyliev and Alireza Khodadadi-Jamayran and Evgeny Nudler and Amaia Lujambio and Lowe, {Scott W.} and Iannis Aifantis and Starczynowski, {Daniel T.}",
note = "Funding Information: This work was supported by the NIH (R01CA216421, R01CA173636, R01CA228135, R01CA242020, 1RO1CA266212, and 1RO1HL159175 to I.A.; R35HL135787, R01DK102759, and R01DK113639 to D.T.S.; L40HL143713 to L.H.L.; and R01CA190261 to S.W.L.), the Edward P. Evans MDS Foundation (I.A.), The Leukemia and Lymphoma Society (T.M. D.T.S. and I.A.), the Uehara Memorial Foundation (T.M.), The NY State Department of Health IDEA and IIRP programs (I.A.), the Waksman Foundation of Japan (T.M.), The Mochida Memorial Foundation for Medical and Pharmaceutical Research (T.M.), Cincinnati Children's Hospital Research Foundation (D.T.S. and L.H.L.), Japan Society for the Promotion of Science (T.M.), Cancer Free Kids (D.T.S. and L.H.L.), and Pelotonia Fellowship (T.M.). M.G. is supported by the American Society of Hematology and Gilead Sciences. S.W.L. is a Howard Hughes Medical Institute investigator. Conceptualization, T.M. M.G. I.A. and D.T.S.; methodology, T.M. M.G. I.A. and D.T.S.; formal data analysis, T.M. M.G. J.Y. J.F. J.B. A.L. L.Z.R. C.S.W. K.H. L.C.B. L.B. L.H.L. E.N. and A.L.; bioinformatic analysis, B.N. Y.G. A.K.-J. and K.C.; supervision, K.D.G. S.W.L. I.A. and D.T.S.; writing, T.M. M.G. I.A. and D.T.S. D.T.S. serves on the scientific advisory board at Kurome Therapeutics and is a consultant for Kymera Therapeutics, Kurome Therapeutics, Captor Therapeutics, and Tolero Therapeutics. D.T.S. has equity in Kurome Therapeutics. The other authors declare no competing interests. Funding Information: This work was supported by the NIH ( R01CA216421 , R01CA173636 , R01CA228135 , R01CA242020 , 1RO1CA266212 , and 1RO1HL159175 to I.A.; R35HL135787 , R01DK102759 , and R01DK113639 to D.T.S.; L40HL143713 to L.H.L.; and R01CA190261 to S.W.L.), the Edward P. Evans MDS Foundation (I.A.), The Leukemia and Lymphoma Society (T.M., D.T.S., and I.A.), the Uehara Memorial Foundation (T.M.), The NY State Department of Health IDEA and IIRP programs (I.A.), the Waksman Foundation of Japan (T.M.), The Mochida Memorial Foundation for Medical and Pharmaceutical Research (T.M.), Cincinnati Children{\textquoteright}s Hospital Research Foundation (D.T.S. and L.H.L.), Japan Society for the Promotion of Science (T.M.), Cancer Free Kids (D.T.S. and L.H.L.), and Pelotonia Fellowship (T.M.). M.G. is supported by the American Society of Hematology and Gilead Sciences . S.W.L. is a Howard Hughes Medical Institute investigator. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2022",
month = feb,
day = "3",
doi = "10.1016/j.stem.2021.12.007",
language = "English",
volume = "29",
pages = "298--314.e9",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "2",
}