Despite 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.
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We thank Drs. A. Thomas Look, David M. Langenau, Anurag Singh, Neil J. Ganem, and Herbert Cohen for helpful discussion and suggestions; as well as Dr. Michael T. Kirber from the Cellular Imaging Core facility at Boston University School of Medicine for his expert help with imaging acquisitions. This study was supported by grants from the NIH (R00CA134743, R56CA215059 and Boston University [BU] pilot grants through 1UL1TR001430 to H.F., R01CA096899 to M.A.K., predoctoral training grant through T32GM008541 to L.N.H.) and fellowship grants from the Rally Foundation and the Alex Lemonade Stand Foundation (N.M.A.). H.F. also acknowledges funding support through a Karin Grunebaum Faculty Fellowship, a BU Ralph Edwards Career Development Professorship, a Young Investigator Award from the Leukemia Research Foundation, a St. Baldrick Scholar grant, and the American Cancer Society (IRG –72-001-36-IRG and RSG-17-204-01-TBG). Y.S., B.L., and J.W.C received the Undergraduate Research Opportunity Program Award at BU. The content of this research is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
H.F. conceived and supervised the project. The experiments were designed by H.F., L.N.H., N.M.A, F.J.F.L., J.E.R., and C.T.L; and performed by L.N.H., Y.S., B.L., Y.W.W., J.W.C., G.L.Z., L.W., C.T.L., and J.E.R.. Data analyses were performed by H.F., L.N.H., L.W., C.T.L., and G.L.Z.. Manuscripts were written by H.F. and L.N.H., and revised by N.M.A., Y.S., B.L., and M.A.K.
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The authors declare that they have no conflict of interest.
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Huiting, L., Samaha, Y., Zhang, G. et al. UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response. Leukemia 32, 2339–2351 (2018). https://doi.org/10.1038/s41375-018-0141-x
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