Publication

Transcriptional regulators CITED2 and PU.1 cooperate in maintaining hematopoietic stem cells

Mattes, K., Geugien, M., Korthuis, P. M., Brouwers-Vos, A. Z., Fehrmann, R. S. N., Todorova, T. I., Steidl, U., Vellenga, E. & Schepers, H., May-2019, In : Experimental Hematology. 73, p. 38-49 12 p.

Research output: Contribution to journalArticleAcademicpeer-review

Copy link to clipboard

Documents

  • Transcriptional regulators CITED2 and PU.1 cooperate in maintaining hematopoietic stem cells

    Final author's version, 12 MB, PDF-document

    Embargo ends: 15/05/2020

    Request copy

  • Transcriptional regulators CITED2 and PU.1 cooperate in maintaining hematopoietic stem cells

    Final publisher's version, 1009 KB, PDF-document

    Request copy

DOI

Reduced expression of the transcription factor PU.1 is frequently associated with development of acute myeloid leukemia (AML), whereas elevated levels of CITED2 (CBP/p300-interacting-transactivator-with-an-ED-rich-tail 2) enhance maintenance of both normal and leukemic hematopoietic stem and progenitor cells (HSPCs). Recent findings indicate that PU.1 and CITED2 act in the same gene regulatory network. We therefore examined a potential synergistic effect of simultaneous PU.1 downregulation and CITED2 upregulation on stem cell biology and AML pathogenesis. We found that simultaneous PU.1/CITED2 deregulation in human CD34(+) cord blood (CB) cells, as well as CITED2 upregulation in preleukemic murine PU.1-knockdown (PU.1(KD/KD)) bone marrow cells, significantly increased the maintenance of HSPCs compared with the respective deregulation of either factor alone. Increased replating capacity of PU.1(KD/KD)/CITED2 cells in in vitro assays eventually resulted in outgrowth of transformed cells, while upregulation of CITED2 in PU.1(KD/KD) cells enhanced their engraftment in in vivo transplantation studies without affecting leukemic transformation. Transcriptional analysis of CD34(+) CB cells with combined PU.1/CITED2 alterations revealed a set of differentially expressed genes that highly correlated with gene signatures found in various AML subtypes. These findings illustrate that combined PU.1/CITED2 deregulation induces a transcriptional program that promotes HSPC maintenance, which might be a prerequisite for malignant transformation. (C) 2019 Published by Elsevier Inc. on behalf of ISEH - Society for Hematology and Stem Cells.

Original languageEnglish
Pages (from-to)38-49
Number of pages12
JournalExperimental Hematology
Volume73
Publication statusPublished - May-2019

    Keywords

  • ACUTE MYELOID-LEUKEMIA, EXPRESSION, MAINTENANCE, PROGENITOR, MUTATIONS, KNOCKDOWN, REDUCTION, DELETION, COMMON, FOXO3A

View graph of relations

ID: 80394503