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Acute lymphoblastic leukemia

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


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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  1. 1.

    Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. Oncogene. 1999;18:3004–16.

    CAS  Article  Google Scholar 

  2. 2.

    Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. 2008;371:1030–43.

    CAS  Article  Google Scholar 

  3. 3.

    Weng AP, Ferrando AA, Lee W, Morris JPT, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306:269–71.

    CAS  Article  Google Scholar 

  4. 4.

    Sharma VM, Calvo JA, Draheim KM, Cunningham LA, Hermance N, Beverly L, et al. Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol Cell Biol. 2006;26:8022–31.

    CAS  Article  Google Scholar 

  5. 5.

    Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 2006;20:2096–109.

    CAS  Article  Google Scholar 

  6. 6.

    Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A, et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA. 2006;103:18261–6.

    CAS  Article  Google Scholar 

  7. 7.

    Sanchez-Martin M, Ferrando A. The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia. Blood. 2017;129:1124–33.

    CAS  Article  Google Scholar 

  8. 8.

    Bhojwani D, Pui CH. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 2013;14:e205–217.

    Article  Google Scholar 

  9. 9.

    Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE, et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell. 2012;151:56–67.

    CAS  Article  Google Scholar 

  10. 10.

    Tu WB, Helander S, Pilstal R, Hickman KA, Lourenco C, Jurisica I, et al. Myc and its interactors take shape. Biochim Biophys Acta. 2015;1849:469–83.

    CAS  Article  Google Scholar 

  11. 11.

    Sabo A, Kress TR, Pelizzola M, de Pretis S, Gorski MM, Tesi A, et al. Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. Nature. 2014;511:488–92.

    CAS  Article  Google Scholar 

  12. 12.

    Yadav RK, Chae SW, Kim HR, Chae HJ. Endoplasmic reticulum stress and cancer. J Cancer Prev. 2014;19:75–88.

    Article  Google Scholar 

  13. 13.

    Kim H, Bhattacharya A, Qi L. Endoplasmic reticulum quality control in cancer: friend or foe. Semin Cancer Biol. 2015;33:25–33.

    CAS  Article  Google Scholar 

  14. 14.

    Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell. 2000;101:249–58.

    CAS  Article  Google Scholar 

  15. 15.

    Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000;2:326–32.

    CAS  Article  Google Scholar 

  16. 16.

    Shen J, Chen X, Hendershot L, Prywes R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell. 2002;3:99–111.

    CAS  Article  Google Scholar 

  17. 17.

    Wolf DH, Stolz A. The Cdc48 machine in endoplasmic reticulum associated protein degradation. Biochim Biophys Acta. 2012;1823:117–24.

    CAS  Article  Google Scholar 

  18. 18.

    Van Vlierberghe P, Ambesi-Impiombato A, De Keersmaecker K, Hadler M, Paietta E, Tallman MS, et al. Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia. Blood. 2013;122:74–82.

    Article  Google Scholar 

  19. 19.

    Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11:619–33.

    CAS  Article  Google Scholar 

  20. 20.

    Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8:519–29.

    CAS  Article  Google Scholar 

  21. 21.

    Hart LS, Cunningham JT, Datta T, Dey S, Tameire F, Lehman SL, et al. ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest. 2012;122:4621–34.

    CAS  Article  Google Scholar 

  22. 22.

    Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30:207–10.

    CAS  Article  Google Scholar 

  23. 23.

    Rosenbloom KR, Sloan CA, Malladi VS, Dreszer TR, Learned K, Kirkup VM, et al. ENCODE data in the UCSC Genome Browser: year 5 update. Nucleic Acids Res. 2013;41:D56–63.

    CAS  Article  Google Scholar 

  24. 24.

    Langenau DM, Feng H, Berghmans S, Kanki JP, Kutok JL, Look AT. Cre/lox-regulated transgenic zebrafish model with conditional myc-induced T cell acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2005;102:6068–73.

    CAS  Article  Google Scholar 

  25. 25.

    Blackburn JS, Liu S, Raiser DM, Martinez SA, Feng H, Meeker ND, et al. Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency. Leukemia. 2012;26:2069–78.

    CAS  Article  Google Scholar 

  26. 26.

    Gutierrez A, Grebliunaite R, Feng H, Kozakewich E, Zhu S, Guo F, et al. Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia. J Exp Med. 2011;208:1595–603.

    CAS  Article  Google Scholar 

  27. 27.

    Amsterdam A, Nissen RM, Sun Z, Swindell EC, Farrington S, Hopkins N. Identification of 315 genes essential for early zebrafish development. Proc Natl Acad Sci USA. 2004;101:12792–7.

    CAS  Article  Google Scholar 

  28. 28.

    Feng H, Langenau DM, Madge JA, Quinkertz A, Gutierrez A, Neuberg DS, et al. Heat-shock induction of T-cell lymphoma/leukaemia in conditional Cre/lox-regulated transgenic zebrafish. Br J Haematol. 2007;138:169–75.

    CAS  Article  Google Scholar 

  29. 29.

    Feng H, Stachura DL, White RM, Gutierrez A, Zhang L, Sanda T, et al. T-lymphoblastic lymphoma cells express high levels of BCL2, S1P1, and ICAM1, leading to a blockade of tumor cell intravasation. Cancer Cell. 2010;18:353–66.

    CAS  Article  Google Scholar 

  30. 30.

    Chen M, Gutierrez GJ, Ronai ZA. Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle control. Proc Natl Acad Sci USA. 2011;108:9119–24.

    CAS  Article  Google Scholar 

  31. 31.

    Beriault DR, Werstuck GH. Detection and quantification of endoplasmic reticulum stress in living cells using the fluorescent compound, Thioflavin T. Biochim Biophys Acta. 2013;1833:2293–301.

    CAS  Article  Google Scholar 

  32. 32.

    Shiu RP, Pouyssegur J, Pastan I. Glucose depletion accounts for the induction of two transformation-sensitive membrane proteinsin Rous sarcoma virus-transformed chick embryo fibroblasts. Proc Natl Acad Sci USA. 1977;74:3840–4.

    CAS  Article  Google Scholar 

  33. 33.

    Lee AS. The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods. 2005;35:373–81.

    CAS  Article  Google Scholar 

  34. 34.

    Elsasser S, Finley D. Delivery of ubiquitinated substrates to protein-unfolding machines. Nat Cell Biol. 2005;7:742–9.

    CAS  Article  Google Scholar 

  35. 35.

    Ballar P, Shen Y, Yang H, Fang S. The role of a novel p97/valosin-containing protein-interacting motif of gp78 in endoplasmic reticulum-associated degradation. J Biol Chem. 2006;281:35359–68.

    CAS  Article  Google Scholar 

  36. 36.

    Woehlbier U, Hetz C. Modulating stress responses by the UPRosome: a matter of life and death. Trends Biochem Sci. 2011;36:329–37.

    CAS  Article  Google Scholar 

  37. 37.

    Ma Y, Brewer JW, Diehl JA, Hendershot LM. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol. 2002;318:1351–65.

    CAS  Article  Google Scholar 

  38. 38.

    McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 2001;21:1249–59.

    CAS  Article  Google Scholar 

  39. 39.

    Kozutsumi Y, Segal M, Normington K, Gething MJ, Sambrook J. The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature. 1988;332:462–4.

    CAS  Article  Google Scholar 

  40. 40.

    Dong D, Stapleton C, Luo B, Xiong S, Ye W, Zhang Y, et al. A critical role for GRP78/BiP in the tumor microenvironment for neovascularization during tumor growth and metastasis. Cancer Res. 2011;71:2848–57.

    CAS  Article  Google Scholar 

  41. 41.

    Mahadevan NR, Zanetti M. Tumor stress inside out: cell-extrinsic effects of the unfolded protein response in tumor cells modulate the immunological landscape of the tumor microenvironment. J Immunol. 2011;187:4403–9.

    CAS  Article  Google Scholar 

  42. 42.

    Shajahan-Haq AN, Cook KL, Schwartz-Roberts JL, Eltayeb AE, Demas DM, Warri AM, et al. MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer. Mol Cancer. 2014;13:239.

    Article  Google Scholar 

  43. 43.

    Ojha R, Amaravadi RK. Targeting the unfolded protein response in cancer. Pharmacol Res. 2017;120:258–66.

    CAS  Article  Google Scholar 

  44. 44.

    Atkins C, Liu Q, Minthorn E, Zhang SY, Figueroa DJ, Moss K, et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2013;73:1993–2002.

    CAS  Article  Google Scholar 

  45. 45.

    Fessart D, Marza E, Taouji S, Delom F, Chevet E. P97/CDC-48: proteostasis control in tumor cell biology. Cancer Lett. 2013;337:26–34.

    CAS  Article  Google Scholar 

  46. 46.

    Dargemont C, Ossareh-Nazari B. Cdc48/p97, a key actor in the interplay between autophagy and ubiquitin/proteasome catabolic pathways. Biochim Biophys Acta. 2012;1823:138–44.

    CAS  Article  Google Scholar 

  47. 47.

    Chen X, Ran ZH, Tong JL, Nie F, Zhu MM, Xu XT, et al. RNA interference (RNAi) of Ufd1 protein can sensitize a hydroxycamptothecin-resistant colon cancer cell line SW1116/HCPT to hydroxycamptothecin. J Dig Dis. 2011;12:110–6.

    CAS  Article  Google Scholar 

  48. 48.

    Uhlen M, Zhang C, Lee S, Sjostedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science 2017; 357:pii: eaan2507.

    Article  Google Scholar 

  49. 49.

    Westerfield M. The Zebrafish Book: A Guide for the Laboratory Use of Zebrafish (Brachydanio rerio). Eugene, OR: University of Oregon Press; 1994.

    Google Scholar 

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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.

Author contributions:

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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Correspondence to H Feng.

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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).

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