CITED2-mediated human hematopoietic stem cell maintenance is critical for acute myeloid leukemia

P. M. Korthuis, G. Berger, B. Bakker, M. Rozenyeld-Geugien, J. Jaques, G. de Haan, J. J. Schuringa, E. Vellenga, H. Schepers*

*Bijbehorende auteur voor dit werk

Onderzoeksoutput: ArticleAcademicpeer review

14 Citaten (Scopus)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)625-635
Aantal pagina's11
TijdschriftLeukemia
Volume29
Nummer van het tijdschrift3
DOI's
StatusPublished - mrt-2015

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