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

Muto, Tomoya, Guillamot, Maria, Yeung, Jennifer, Fang, Jing, Bennett, Joshua, Nadorp, Bettina, Lasry, Audrey, Redondo, Luna Zea, Choi, Kwangmin, Gong, Yixiao, Walker, Callum S, Hueneman, Kathleen, Bolanos, Lyndsey C, Barreyro, Laura, Lee, Lynn H, Greis, Kenneth D, Vasyliev, Nikita, Khodadadi-Jamayran, Alireza, Nudler, Evgeny, Lujambio, Amaia, Lowe, Scott W, Aifantis, Iannis, Starczynowski, Daniel T (February 2022) TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity. Cell Stem Cell, 29 (2). 298-314.e9. ISSN 1934-5909

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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.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > cancer > cancer types > acute myeloid leukemia bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types diseases & disorders > inflammation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor diseases & disorders > cancer > cancer types
CSHL Authors:	Lowe, Scott W.
Communities:	CSHL labs > Lowe lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	3 February 2022
Date Deposited:	03 Oct 2023 21:15
Last Modified:	16 Jan 2024 19:16
PMCID:	PMC8822959
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41127

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