Huiting, L.N.Samaha, Y.Zhang, GuanglanRoderick, J.E.Li, B.Anderson, N.M.Wang, Y.W.Wang, L.Laroche, F.J.F.Choi, J.W.Liu, C.T.Kelliher, M.A.Feng, Hui2019-10-082019-10-082018-04-25L.N. Huiting, Y. Samaha, G. Zhang, J.E. Roderick, B. Li, N.M. Anderson, Y.W. Wang, L. Wang, F.J.F. Laroche, J.W. Choi, C.T. Liu, M.A. Kelliher, H. Feng. 2018. "UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response." Leukemia, Volume 32, pp. 2339 - 2351. https://doi.org/10.1038/s41375-018-0141-x0887-6924https://hdl.handle.net/2144/38224Despite the pivotal role of MYC in tumorigenesis, the mechanisms by which it promotes cancer aggressiveness remain incompletely understood. Here, we show that MYC transcriptionally upregulates the ubiquitin fusion degradation 1 (UFD1) gene in T-cell acute lymphoblastic leukemia (T-ALL). Allelic loss of ufd1 in zebrafish induces tumor cell apoptosis and impairs MYC-driven T-ALL progression but does not affect general health. As the E2 component of an endoplasmic reticulum (ER)-associated degradation (ERAD) complex, UFD1 facilitates the elimination of misfolded/unfolded proteins from the ER. We found that UFD1 inactivation in human T-ALL cells impairs ERAD, exacerbates ER stress, and induces apoptosis. Moreover, we show that UFD1 inactivation promotes the proapoptotic unfolded protein response (UPR) mediated by protein kinase RNA-like ER kinase (PERK). This effect is demonstrated by an upregulation of PERK and its downstream effector C/EBP homologous protein (CHOP), as well as a downregulation of BCL2 and BCLxL. Indeed, CHOP inactivation or BCL2 overexpression is sufficient to rescue tumor cell apoptosis induced by UFD1 knockdown. Together, our studies identify UFD1 as a critical regulator of the ER stress response and a novel contributor to MYC-mediated leukemia aggressiveness, with implications for targeted therapy in T-ALL and likely other MYC-driven cancers.p. 2339 - 2351Acute lymphocytic leukemiaCancer microenvironmentLife sciences & biomedicineOncologyHematologyAnimalsApoptosisCell line, tumorDisease progressionDown-regulationEndoplasmic reticulumEndoplasmic reticulum stressFemaleHumansMaleProteinsProto-oncogene proteins c-mycTranscription factor CHOPTranscription, geneticTranscriptional activationUbiquitinUnfolded protein responseUp-regulationZebrafisheIF-2 kinaseClinical sciencesOncology and carcinogenesisImmunologyArticle10.1038/s41375-018-0141-x0000-0001-6010-490X (Zhang, G)332256