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Leukemia. 2018 Apr 25. doi: 10.1038/s41375-018-0141-x. [Epub ahead of print]

UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response.

Author information

1
Departments of Pharmacology and Medicine, Cancer Research Center, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA.
2
Department of Computer Science, Metropolitan College, Boston University, Boston, MA, USA.
3
Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA, USA.
4
Department of Molecular, Cell and Cancer Biology, University of Massachusetts School of Medicine, Worcester, MA, USA.
5
Department of Anatomy and Embryology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, P. R. China.
6
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
7
Departments of Pharmacology and Medicine, Cancer Research Center, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, USA. huifeng@bu.edu.

Abstract

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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