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Ann Hematol. 2019 Jun 16. doi: 10.1007/s00277-019-03726-7. [Epub ahead of print]

BOK promotes erythropoiesis in a mouse model of myelodysplastic syndrome.

Author information

1
Department of Laboratory Medicine, Chosun University College of Medicine, Gwangju, Republic of Korea.
2
Department of Pathology, Yale University School of Medicine, 310 Cedar Street, LH 315B, New Haven, CT, 06520, USA.
3
Department of Pathology, Yale University School of Medicine, 310 Cedar Street, LH 315B, New Haven, CT, 06520, USA. Samuel.Katz@yale.edu.

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.

KEYWORDS:

Apoptosis; BCL-2; BOK; Erythropoiesis; Myelodysplasia

PMID:
31203423
DOI:
10.1007/s00277-019-03726-7

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