Role of the Polycomb Gene Bcor in Hematopoiesis

• Published in: Blood 2014-12, Vol.124 (21), p.4312-4312
• Main Authors: Tanaka, Tomoyuki, Nakajima-Takagi, Yaeko, Si, Sha, Saraya, Atsunori, Hirohito, Sone, Koseki, Haruhiko, Iwama, Atsushi
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.4312.4312

Polycomb group (PcG) proteins are epigenetic regulators crucial for the maintenance and differentiation of stem cells. PcG proteins form in the nucleus two kinds of complexes, PRC (polycomb repressive complex) 1 containing Pcgf family proteins and PRC2. PRC1 ubiquitylates histone H2A at lysine 119 and PRC2 trimethylates lysine 27 of histone H3. Bcor (BCL6 corepressor) together with Pcgf1 has recently been demonstrated to form a non-canonical PRC1 distinct from canonical PRC1 containing Cbx and Bmi1/Pcgf4. Of note, recurrent somatic mutations have been identified in BCOR in myeloid malignancies such as acute myeloid leukemia and myelodysplastic syndrome. However, little is known about its role in hematopoiesis and hematological malignancies. In this study, we investigated the role of Bcor in hematopoiesis using Bcor conditional knockout mice. We first examined basal levels of Bcor expression in BM hematopoietic cell populations by real-time qPCR and found that Bcor is ubiquitously expressed with the highest expression in Flk2-CD34+c-Kit+Sca-1+Lineage- ST-HSCs. We transplanted total bone marrow (BM) cells (CD45.2+) from Bcor floxed male mice (Bcorf/Y ; Bcor is located at X chromosome) crossed with Rosa::Cre-ERT mice into lethally irradiated recipient mice with the equal numbers of BM cells from CD45.1+ congenic WT mice and deleted Bcor by inducing nuclear translocation of Cre by tamoxifen injection at 4 weeks post-transplantation. Chimerism of Bcor-/Y cells in the peripheral blood gradually decreased in all lineages by 6 months after tamxifen injection. BM analysis also showed decreased chimerism of Bcor-/Y cells in Lineage-Sca-1+c-Kit+ (LSK) HSCs/MPPs and myeloid progenitors at 7 months after tamoxifen injection. In non-competitive repopulating assays, recipient mice repopulated with Bcor-/Y BM cells showed leukopenia mainly due to impaired B lymphopoiesis. BM analysis showed CD34-LSK HSC number was significantly decreased in recipients repopulated with Bcor-/Y BM cells compared to the controls. However, no mice showed any signs of myeloid malignancies. These data suggested that Bcor is essential for the maintenance of repopulating capacity of HSCs. We then examined the effects of deletion of Bcor on HSC growth in vitro. Bcor-/Y CD34-LSK cells were cultured for 14 days. Deletion of Bcor profoundly impaired the growth of CD34-LSK cells in the presence of SCF, TPO and IL3 but not significantly in the presence of SCF and TPO only. This finding suggests that Bc