title: The Runx-PU.1 pathway preserves normal and AML/ETO9a leukemic stem cells.
abstract: Runx transcription factors contribute to hematopoiesis and are frequently implicated in hematologic malignancies. All three Runx isoforms are expressed at the earliest stages of hematopoiesis; however, their function in hematopoietic stem cells (HSCs) is not fully elucidated. Here, we show that Runx factors are essential in HSCs by driving the expression of the hematopoietic transcription factor PU.1. Mechanistically, by using a knockin mouse model in which all three Runx binding sites in the -14kb enhancer of PU.1 are disrupted, we observed failure to form chromosomal interactions between the PU.1 enhancer and its proximal promoter. Consequently, decreased PU.1 levels resulted in diminished long-term HSC function through HSC exhaustion, which could be rescued by reintroducing a PU.1 transgene. Similarly, in a mouse model of AML/ETO9a leukemia, disrupting the Runx binding sites resulted in decreased PU.1 levels. Leukemia onset was delayed, and limiting dilution transplantation experiments demonstrated functional loss of leukemia-initiating cells. This is surprising, because low PU.1 levels have been considered a hallmark of AML/ETO leukemia, as indicated in mouse models and as shown here in samples from leukemic patients. Our data demonstrate that Runx-dependent PU.1 chromatin interaction and transcription of PU.1 are essential for both normal and leukemia stem cells.
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA; Division of Hematology and Hemostaseology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria;
authors.forename: Philipp B
authors.initials: PB
authors.lastname: Staber
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA;
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA;
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA;
authors.forename: Robert S
authors.initials: RS
authors.lastname: Welner
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA; Institute of Biomedical Technologies, National Research Council, Pisa, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Levantini
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA;
authors.forename: Annalisa
authors.initials: A
authors.lastname: Di Ruscio
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA;
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Ebralidze
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA;
authors.forename: Christian
authors.initials: C
authors.lastname: Bach
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA;
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA;
authors.forename: Junyan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Hematology and Hemostaseology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna, Austria;
authors.forename: Katrina
authors.initials: K
authors.lastname: Vanura
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore; and.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.affiliation: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA; Cancer Science Institute, National University of Singapore, Singapore; and.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
mesh_terms: D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001665:Binding Sites; D050657:Core Binding Factor alpha Subunits / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D050657:Core Binding Factor alpha Subunits; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1