Mouse RUNX1C regulates pre-megakaryocytic/erythroid output and maintains survival of megakaryocyte progenitors.
AuthorsDraper, Julia E
Leong, Hui Sun
Fadlullah, Muhammad Z H
Miller, Crispin J
AffiliationCancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester
MetadataShow full item record
AbstractRUNX1 is crucial for the regulation of megakaryocyte specification, maturation and thrombopoiesis. Runx1 possesses two promoters: the distal P1 and proximal P2 promoters. The major protein isoforms generated by P1 and P2 are RUNX1C and RUNX1B respectively, which differ solely in their N-terminal amino acid sequences. RUNX1C is the most abundantly expressed isoform in adult hematopoiesis, present in all RUNX1-expressing populations, including the cKit(+) hematopoietic stem and progenitor cells (HSPCs). RUNX1B expression is more restricted, being highly expressed in the megakaryocyte lineage but downregulated during erythropoiesis. We generated a Runx1P1 knock-in of RUNX1B, termed P1-MRIPV This mouse line lacks RUNX1C expression but has normal total RUNX1 levels, solely comprising RUNX1B. Utilizing this mouse line we establish a specific requirement for the P1-RUNX1C isoform in megakaryopoiesis, which cannot be entirely compensated for by RUNX1B overexpression. P1 knock-in Megakaryocyte Progenitors (MkP) have reduced proliferative capacity and undergo increased cell death, resulting in thrombocytopenia. P1 knock-in Pre-Megakaryocyte/Erythroid Progenitors (PreMegEs) demonstrate an erythroid-specification bias, evident from increased erythroid colony-forming ability and decreased megakaryocyte output. At a transcriptional level, multiple erythroid-specific genes are upregulated and megakaryocyte-specific transcripts are downregulated. In addition, pro-apoptotic pathways are activated in P1 knock-in PreMegEs, presumably accounting for the increased cell death in the MkP compartment. Unlike in the conditional adult Runx1 null models, megakaryocytic maturation is not affected in the P1 knock-in mice, suggesting that RUNX1B can regulate endomitosis and thrombopoiesis. Therefore, despite the high degree of structural similarity, RUNX1B and RUNX1C isoforms have distinct and specific roles in adult megakaryopoiesis.
CitationMouse RUNX1C regulates pre-megakaryocytic/erythroid output and maintains survival of megakaryocyte progenitors. 2017 Blood
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