CITED2-mediated human hematopoietic stem cell maintenance is critical for acute myeloid leukemia.
Leukemia, 2015/3;29(3):625-35.
Korthuis PM[1], Berger G[1], Bakker B[1], Rozenveld-Geugien M[1], Jaques J[1], de Haan G[2], Schuringa JJ[1], Vellenga E[1], Schepers H[1]
Affiliations
PMID: 25184385DOI: 10.1038/leu.2014.259
Impact factor: 12.883
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.
MeSH terms
Animals; Antigens, CD34; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Female; Gene Expression Regulation, Leukemic; Graft Survival; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; Mutation; Proto-Oncogene Proteins; Repressor Proteins; Signal Transduction; Trans-Activators; Transplantation, Heterologous; DNA Methyltransferase 3B
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