title: CITED2-mediated human hematopoietic stem cell maintenance is critical for acute myeloid leukemia.
abstract: As the transcriptional coactivator CITED2 (CBP/p300-interacting-transactivator-with-an ED-rich-tail 2) can be overexpressed in acute myeloid leukemia (AML) cells, we analyzed the consequences of high CITED2 expression in normal and AML cells. CITED2 overexpression in normal CD34(+) cells resulted in enhanced hematopoietic stem and progenitor cell (HSPC) output in vitro, as well as in better hematopoietic stem cell (HSC) engraftability in NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice. This was because of an enhanced quiescence and maintenance of CD34(+)CD38(-) HSCs, due in part to an increased expression of the cyclin-dependent kinase inhibitor CDKN1A. We demonstrated that PU.1 is a critical regulator of CITED2, as PU.1 repressed CITED2 expression in a DNA methyltransferase 3A/B (DNMT3A/B)-dependent manner in normal CD34(+) cells. CD34(+) cells from a subset of AML patients displayed higher expression levels of CITED2 as compared with normal CD34(+) HSPCs, and knockdown of CITED2 in AML CD34(+) cells led to a loss of long-term expansion, both in vitro and in vivo. The higher CITED2 expression resulted from reduced PU.1 activity and/or dysfunction of mutated DNMT3A/B. Collectively, our data demonstrate that increased CITED2 expression results in better HSC maintenance. In concert with low PU.1 levels, this could result in a perturbed myeloid differentiation program that contributes to leukemia maintenance.
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: P M
authors.initials: PM
authors.lastname: Korthuis
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Berger
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Bakker
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Rozenveld-Geugien
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Jaques
authors.affiliation: Department of Stem Cell Biology, European Research Institute for the Biology of Aging (ERIBA), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: de Haan
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Schuringa
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Vellenga
authors.affiliation: Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Schepers
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D000097584:DNA Methyltransferase 3B; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D018952:Antigens, CD34; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D000097584:DNA Methyltransferase 3B; D000099232:Proto-Oncogene Protein Spi-1; C493956:CDKN1A protein, human; C486381:CITED2 protein, human; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse