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BOK promotes erythropoiesis in a mouse model of myelodysplastic syndrome

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Abstract

Myelodysplastic syndromes are clonal hematopoietic stem cell disorders characterized by cytopenia and intramedullary apoptosis. BCL-2 Ovarian Killer (BOK) is a pro-apoptotic member of the BCL-2 family of proteins which, when stabilized from endoplasmic reticulum-associated degradation (ERAD), induces apoptosis in response to ER stress. Although ER stress appropriately activates the unfolded protein response (UPR) in BOK-disrupted cells, the downstream effector signaling that includes ATF4 is defective. We used Nup98-HoxD13 (NHD13) transgenic mice to evaluate the consequences of BOK loss on hematopoiesis and leukemogenesis. Acute myeloid leukemia developed in 36.7% of NHD13 mice with a Bok gene knockout between the age of 8 and 13 months and presented a similar overall survival to the NHD13 mice. The loss of BOK exacerbated anemia in NHD13 mice, and NHD13/BOK-deficient mice exhibited significantly lower hemoglobin, lower mean cell hemoglobin concentration, and higher mean cell volume than NHD13 mice. Hematopoietic progenitor cell assays revealed a decreased amount of erythroid progenitor stem cells (BFU-E) in the bone marrow of NHD13-transgenic/BOK-deficient mice. RT-qPCR analysis demonstrated decreased mean value of ATF4 in the erythroid progenitors of NHD13 and NHD13/BOK-deficient mice. Our results suggest that in addition to induction of apoptosis in response to ER stress, BOK may regulate erythropoiesis when certain erythroid progenitors experience cell stress.

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References

  1. Horiike S, Kita-Sasai Y, Nakao M, Taniwaki M (2003) Configuration of the TP53 gene as an independent prognostic parameter of myelodysplastic syndrome. Leuk Lymphoma 44(6):915–922

    Article  CAS  PubMed  Google Scholar 

  2. Kaneko H, Misawa S, Horiike S, Nakai H, Kashima K (1995) TP53 mutations emerge at early phase of myelodysplastic syndrome and are associated with complex chromosomal abnormalities. Blood 85(8):2189–2193

    CAS  PubMed  Google Scholar 

  3. Ludwig L, Schulz AS, Janssen JW, Grunewald K, Bartram CR (1992) P53 mutations in myelodysplastic syndromes. Leukemia 6(12):1302–1304

    CAS  PubMed  Google Scholar 

  4. Sugimoto K, Hirano N, Toyoshima H, Chiba S, Mano H, Takaku F, Yazaki Y, Hirai H (1993) Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia. Blood 81(11):3022–3026

    CAS  PubMed  Google Scholar 

  5. Yakovlev AG, Di Giovanni S, Wang G, Liu W, Stoica B, Faden AI (2004) BOK and NOXA are essential mediators of p53-dependent apoptosis. J Biol Chem 279(27):28367–28374

    Article  CAS  PubMed  Google Scholar 

  6. Hsu SY, Kaipia A, McGee E, Lomeli M, Hsueh AJ (1997) Bok is a pro-apoptotic Bcl-2 protein with restricted expression in reproductive tissues and heterodimerizes with selective anti-apoptotic Bcl-2 family members. Proc Natl Acad Sci U S A 94(23):12401–12406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Echeverry N, Bachmann D, Ke F, Strasser A, Simon HU, Kaufmann T (2013) Intracellular localization of the BCL-2 family member BOK and functional implications. Cell Death Differ 20(6):785–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Llambi F, Wang YM, Victor B, Yang M, Schneider DM, Gingras S, Parsons MJ, Zheng JH, Brown SA, Pelletier S, Moldoveanu T, Chen T, Green DR (2016) BOK is a non-canonical BCL-2 family effector of apoptosis regulated by ER-associated degradation. Cell 165(2):421–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Carpio MA, Michaud M, Zhou W, Fisher JK, Walensky LD, Katz SG (2015) BCL-2 family member BOK promotes apoptosis in response to endoplasmic reticulum stress. Proc Natl Acad Sci U S A 112(23):7201–7206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334(6059):1081–1086

    Article  CAS  PubMed  Google Scholar 

  11. Rabachini T, Fernandez-Marrero Y, Montani M, Loforese G, Sladky V, He Z, Bachmann D, Wicki S, Villunger A, Stroka D, Kaufmann T (2018) BOK promotes chemical-induced hepatocarcinogenesis in mice. Cell Death Differ 25(4):706–718

    Article  CAS  Google Scholar 

  12. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, Tsao MS, Demichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463(7283):899–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Moravcikova E, Krepela E, Donnenberg VS, Donnenberg AD, Benkova K, Rabachini T, Fernandez-Marrero Y, Bachmann D, Kaufmann T (2017) BOK displays cell death-independent tumor suppressor activity in non-small-cell lung carcinoma. Int J Cancer 141(10):2050–2061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kentsis A, Reed C, Rice KL, Sanda T, Rodig SJ, Tholouli E, Christie A, Valk PJ, Delwel R, Ngo V, Kutok JL, Dahlberg SE, Moreau LA, Byers RJ, Christensen JG, Vande Woude G, Licht JD, Kung AL, Staudt LM, Look AT (2012) Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nat Med 18(7):1118–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ke F, Voss A, Kerr JB, O'Reilly LA, Tai L, Echeverry N, Bouillet P, Strasser A, Kaufmann T (2012) BCL-2 family member BOK is widely expressed but its loss has only minimal impact in mice. Cell Death Differ 19(6):915–925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lin YW, Slape C, Zhang Z, Aplan PD (2005) NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia. Blood 106(1):287–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Slape C, Liu LY, Beachy S, Aplan PD (2008) Leukemic transformation in mice expressing a NUP98-HOXD13 transgene is accompanied by spontaneous mutations in Nras, Kras, and Cbl. Blood 112(5):2017–2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Guirguis AA, Slape CI, Failla LM, Saw J, Tremblay CS, Powell DR, Rossello F, Wei A, Strasser A, Curtis DJ (2016) PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia. Cell Death Differ 23(6):1049–1059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Slape CI, Saw J, Jowett JB, Aplan PD, Strasser A, Jane SM, Curtis DJ (2012) Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome. Blood 120(12):2475–2483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen JJ (2014) Translational control by heme-regulated eIF2alpha kinase during erythropoiesis. Curr Opin Hematol 21(3):172–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen K, Liu J, Heck S, Chasis JA, An X, Mohandas N (2009) Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc Natl Acad Sci U S A 106(41):17413–17418

    Article  PubMed  PubMed Central  Google Scholar 

  22. Suragani RN, Zachariah RS, Velazquez JG, Liu S, Sun CW, Townes TM, Chen JJ (2012) Heme-regulated eIF2alpha kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis. Blood 119(22):5276–5284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dolznig H, Boulme F, Stangl K, Deiner EM, Mikulits W, Beug H, Mullner EW (2001) Establishment of normal, terminally differentiating mouse erythroid progenitors: molecular characterization by cDNA arrays. FASEB J 15(8):1442–1444

    Article  CAS  PubMed  Google Scholar 

  24. Carberry S, D'Orsi B, Monsefi N, Salvucci M, Bacon O, Fay J, Rehm M, McNamara D, Kay EW, Prehn JHM (2018) The BAX/BAK-like protein BOK is a prognostic marker in colorectal cancer. Cell Death Dis 9(2):125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Masuoka HC, Townes TM (2002) Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood 99(3):736–745

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the NHLBI Grant 1R01HL131793, the NIDDK Grant U54DK106857, a Gabrielle’s Angel Foundation award, the Leukemia Research Foundation, and the March of Dimes Basil O’Connor Starter Scholar research award. This work was also supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B07040319).

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Authors and Affiliations

  1. Department of Laboratory Medicine, Chosun University College of Medicine, Gwangju, Republic of Korea

    Seong-Ho Kang

  2. Department of Pathology, Yale University School of Medicine, 310 Cedar Street, LH 315B, New Haven, CT, 06520, USA

    Oscar Perales, Michael Michaud & Samuel G. Katz

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  1. Seong-Ho Kang
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  2. Oscar Perales
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  3. Michael Michaud
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  4. Samuel G. Katz
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Corresponding author

Correspondence to Samuel G. Katz.

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All human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All procedures performed in studies involving animals were in accordance with the ethical standards of Yale University (2018-11514).

Conflict of interest

S-H. K., O.P., and M.M. declare no conflict of interest. S.G.K. serves as a SAB member for Dansar IT and Gene-in-Cell.

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Kang, SH., Perales, O., Michaud, M. et al. BOK promotes erythropoiesis in a mouse model of myelodysplastic syndrome. Ann Hematol 98, 2089–2096 (2019). https://doi.org/10.1007/s00277-019-03726-7

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  • DOI: https://doi.org/10.1007/s00277-019-03726-7

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