TY - JOUR
T1 - Transcriptional regulators CITED2 and PU.1 cooperate in maintaining hematopoietic stem cells
AU - Mattes, Katharina
AU - Geugien, Marjan
AU - Korthuis, Patrick M.
AU - Brouwers-Vos, Annet Z.
AU - Fehrmann, Rudolf S.N.
AU - Todorova, Tihomira I.
AU - Steidl, Ulrich
AU - Vellenga, Edo
AU - Schepers, Hein
N1 - Funding Information:
We acknowledge W. Abdulahad, T. Bijma, H. Moes, J. Teunis, and G. Mesander for help with flow cytometry. We greatly appreciate the help of Dr. A. van Loon, Dr. J. J. Erwich, and colleagues (Obstetrics Departments of the Martini Hospital and UMCG) for collecting cord blood. This work was funded by an NWO VENI grant (91611105) awarded to HS and a Tekke Huizinga grant (STHF-157) awarded to KM. The authors declare no competing financial interests.
Funding Information:
We acknowledge W. Abdulahad, T. Bijma, H. Moes, J. Teunis, and G. Mesander for help with flow cytometry. We greatly appreciate the help of Dr. A. van Loon, Dr. J. J. Erwich, and colleagues (Obstetrics Departments of the Martini Hospital and UMCG) for collecting cord blood. This work was funded by an NWO VENI grant ( 91611105 ) awarded to HS and a Tekke Huizinga grant ( STHF-157 ) awarded to KM.
Publisher Copyright:
© 2019
PY - 2019/5
Y1 - 2019/5
N2 - 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.1KD/KD) bone marrow cells, significantly increased the maintenance of HSPCs compared with the respective deregulation of either factor alone. Increased replating capacity of PU.1KD/KD/CITED2 cells in in vitro assays eventually resulted in outgrowth of transformed cells, while upregulation of CITED2 in PU.1KD/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.
AB - 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.1KD/KD) bone marrow cells, significantly increased the maintenance of HSPCs compared with the respective deregulation of either factor alone. Increased replating capacity of PU.1KD/KD/CITED2 cells in in vitro assays eventually resulted in outgrowth of transformed cells, while upregulation of CITED2 in PU.1KD/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.
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U2 - 10.1016/j.exphem.2019.03.003
DO - 10.1016/j.exphem.2019.03.003
M3 - Article
C2 - 30986495
AN - SCOPUS:85064847209
SN - 0301-472X
VL - 73
SP - 38-49.e7
JO - Experimental Hematology
JF - Experimental Hematology
ER -
