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BOK promotes erythropoiesis in a mouse model of myelodysplastic syndrome

Annals of Hematology volume 98, pages 2089–2096 (2019)Cite this article

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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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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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

Authors
  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.

Ethics declarations

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

Keywords

  • BCL-2
  • BOK
  • Myelodysplasia
  • Erythropoiesis
  • Apoptosis