TY - JOUR
T1 - Inability of RUNX1/AML1 to breach AML1-ETO block of embryonic stem cell definitive hematopoiesis
AU - Peterson, Luke F.
AU - Lo, Miao Chia
AU - Okumura, Akiko Joo
AU - Zhang, Dong Er
N1 - Funding Information:
We thank Dr. Gordon Keller for providing the LIF producing cell line. This work was supported by National Institute of Health grant CA096735 (DEZ). MCL is a postdoctoral fellow of Leukemia and Lymphoma Society. The Stein Endowment Fund has partially supported MEM departmental molecular biology service laboratory for DNA sequencing and oligonucleotide synthesis. This is manuscript 18968 from The Scripps Research Institute.
PY - 2007/11
Y1 - 2007/11
N2 - The t(8;21)(q22:q22) translocation associated with acute myeloid leukemia fuses the AML1/RUNX1 N-terminal portion located on chromosome 21 to most of the ETO/MTG8 gene on chromosome 8. Various investigators have shown that the fusion product AML1-ETO on its own is unable to promote leukemia. Early studies using transgenic mouse models demonstrated that the direct knock-in of the fusion protein expression is embryonic lethal, similar to the AML1 knockout, suggesting that AML1-ETO has a dominant negative role over AML1. Using the embryonic stem cells generated for such studies, we show here that the presence of the fusion product AML1-ETO blocks definitive hematopoiesis in vitro as well, in both one and two step methylcellulose methods of embryonic stem cell hematopoietic differentiation. However, there is a very low occurrence of macrophage colonies, similar to the knock-in mice that display macrophages in cell cultures of yolk sac derived cells. In addition, we show that exogenous expression of AML1 is unable to bypass this AML1-ETO induced definitive hematopoietic block in these cells. This inability is not linked to an inability to reverse gene expression inhibition by AML1-ETO of the PU.1 gene associated with stem cell maintenance and myeloid differentiation. Our results suggest that AML1-ETO functions in a complex competitive manner with AML1 involving transcriptional regulation, protein-protein interactions and post-transcriptional mechanism(s) affecting early embryonic hematopoiesis and possibly leukemogenesis.
AB - The t(8;21)(q22:q22) translocation associated with acute myeloid leukemia fuses the AML1/RUNX1 N-terminal portion located on chromosome 21 to most of the ETO/MTG8 gene on chromosome 8. Various investigators have shown that the fusion product AML1-ETO on its own is unable to promote leukemia. Early studies using transgenic mouse models demonstrated that the direct knock-in of the fusion protein expression is embryonic lethal, similar to the AML1 knockout, suggesting that AML1-ETO has a dominant negative role over AML1. Using the embryonic stem cells generated for such studies, we show here that the presence of the fusion product AML1-ETO blocks definitive hematopoiesis in vitro as well, in both one and two step methylcellulose methods of embryonic stem cell hematopoietic differentiation. However, there is a very low occurrence of macrophage colonies, similar to the knock-in mice that display macrophages in cell cultures of yolk sac derived cells. In addition, we show that exogenous expression of AML1 is unable to bypass this AML1-ETO induced definitive hematopoietic block in these cells. This inability is not linked to an inability to reverse gene expression inhibition by AML1-ETO of the PU.1 gene associated with stem cell maintenance and myeloid differentiation. Our results suggest that AML1-ETO functions in a complex competitive manner with AML1 involving transcriptional regulation, protein-protein interactions and post-transcriptional mechanism(s) affecting early embryonic hematopoiesis and possibly leukemogenesis.
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U2 - 10.1016/j.bcmd.2007.06.012
DO - 10.1016/j.bcmd.2007.06.012
M3 - Article
C2 - 17692541
AN - SCOPUS:34748891719
SN - 1079-9796
VL - 39
SP - 321
EP - 328
JO - Blood Cells, Molecules, and Diseases
JF - Blood Cells, Molecules, and Diseases
IS - 3
ER -