BOK promotes erythropoiesis in a mouse model of myelodysplastic syndrome.
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.
['Kang|Seong-Ho|SH|', 'Perales|Oscar|O|', 'Michaud|Michael|M|', 'Katz|Samuel G|SG|']
D000818:Animals D017209:Apoptosis D004195:Disease Models, Animal D059865:Endoplasmic Reticulum Stress D060746:Endoplasmic Reticulum-Associated Degradation D015672:Erythroid Precursor Cells D004920:Erythropoiesis D006454:Hemoglobins D051379:Mice D018345:Mice, Knockout D009190:Myelodysplastic Syndromes D019253:Proto-Oncogene Proteins c-bcl-2
BOK Erythropoiesis Apoptosis BCL-2 Myelodysplasia