title: Runx1 loss minimally impacts long-term hematopoietic stem cells.
abstract: RUNX1 encodes a DNA binding subunit of the core-binding transcription factors and is frequently mutated in acute leukemia, therapy-related leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia. Mutations in RUNX1 are thought to confer upon hematopoietic stem cells (HSCs) a pre-leukemic state, but the fundamental properties of Runx1 deficient pre-leukemic HSCs are not well defined. Here we show that Runx1 deficiency decreases both apoptosis and proliferation, but only minimally impacts the frequency of long term repopulating HSCs (LT-HSCs). It has been variously reported that Runx1 loss increases LT-HSC numbers, decreases LT-HSC numbers, or causes age-related HSC exhaustion. We attempt to resolve these discrepancies by showing that Runx1 deficiency alters the expression of several key HSC markers, and that the number of functional LT-HSCs varies depending on the criteria used to score them. Finally, we identify genes and pathways, including the cell cycle and p53 pathways that are dysregulated in Runx1 deficient HSCs.
authors.affiliation: Abramson Family Cancer Research Institute and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Cai
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Gaudet
authors.forename: James K
authors.initials: JK
authors.lastname: Mangan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chen
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: De Obaldia
authors.forename: Zaw
authors.initials: Z
authors.lastname: Oo
authors.forename: Patricia
authors.initials: P
authors.lastname: Ernst
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Speck
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D015415:Biomarkers; D050676:Core Binding Factor Alpha 2 Subunit; C493726:Runx1 protein, mouse; C045073:Cre recombinase; D019426:Integrases