BOK promotes erythropoiesis in a mouse model of myelodysplastic syndrome

Ann Hematol. 2019 Sep;98(9):2089-2096. doi: 10.1007/s00277-019-03726-7. Epub 2019 Jun 16.

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.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress*
  • Endoplasmic Reticulum-Associated Degradation*
  • Erythroid Precursor Cells / metabolism*
  • Erythroid Precursor Cells / pathology
  • Erythropoiesis*
  • Hemoglobins / metabolism
  • Mice
  • Mice, Knockout
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / metabolism*
  • Myelodysplastic Syndromes / pathology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*

Substances

  • Bok protein, mouse
  • Hemoglobins
  • Proto-Oncogene Proteins c-bcl-2