Zbtb1 prevents default myeloid differentiation of lymphoid-primed multipotent progenitors

// Xianyu Zhang 1 , Ying Lu 1 , Xin Cao 2 , Tao Zhen 3 and Damian Kovalovsky 1 1 Experimental Immunology Branch, NCI, NIH, Maryland, USA 2 College of Life Science and Engineering, Northwest University for Nationalities, Gansu Engineering Research Center for Animal Cell, Lanzhou, China 3 Oncogenesis and Development Section, National Human Genome Research Institute, NIH, Maryland, USA Correspondence to: Damian Kovalovsky, email: // Keywords : Zbtb1, lymphoid, development, myeloid, differentiation, Immunology and Microbiology Section, Immune response, Immunity Received : June 18, 2016 Accepted : August 02, 2016 Published : August 17, 2016 Abstract Zbtb1 is a transcription factor that prevents DNA damage and p53-mediated apoptosis in replicating immune progenitors, affecting lymphoid as well as myeloid development when hematopoietic progenitors are in competition in mixed bone marrow chimeras. However, Zbtb1-deficient mice do not have an apparent myeloid deficiency. We report here that Zbtb1-deficient lymphoid-primed multipotent progenitors (LMPPs) are biased to develop towards the myeloid fate in detriment of lymphoid development, contributing to the apparent unaffected myeloid development. Zbtb1 expression was maintained during lymphoid development of LMPP cells but downregulated during myeloid development. Deficiency of Zbtb1 in LMPP cells was sufficient to direct a myeloid fate in lymphoid-inducing conditions and in the absence of myeloid cytokines as shown by upregulation of a myeloid gene signature and the generation of myeloid cells in vitro . Finally, biased myeloid differentiation of Zbtb1-deficient LMPP cells was not due to increased p53-dependent apoptosis as it was not reverted by transgenic Bcl2 expression or p53 deficiency. Altogether, our results show that Zbtb1 expression prevents activation of a default myeloid program in LMPP cells, ensuring the generation of lymphoid cells.