TY - JOUR
T1 - The ETO domain is necessary for the developmental abnormalities associated with AML1-ETO expression in the hematopoietic stem cell compartment in vivo
AU - De Guzman, Cristina G.
AU - Johnson, Amanda
AU - Klug, Christopher A.
N1 - Funding Information:
We thank Dr. Larry Gartland for expert assistance with the flow cytometer and the animal care personnel in the Wallace Tumor Institute. We are also grateful for support from the Division of Developmental and Clinical Immunology and members of the Klug laboratory. This work was supported by a Howard Hughes Faculty Development Award to C.A.K. (53000281) and a Molecular and Viral Oncology Predoctoral Training Grant to C.G.d. (5T32CA09467) This paper is based on a presentation at a Focused Workshop on “Transcriptional Regulation RUNX Proteins in Development and Leukemia” held at the University of Virginia on August 25–27, 2002, sponsored by The Leukemia & Lymphoma Society.
PY - 2003
Y1 - 2003
N2 - Translocation of the ETO gene on human chromosome 8 with the AML1 gene on chromosome 21 (AML1-ETO) is a recurrent cytogenetic abnormality associated with approximately 12% of acute myelogenous leukemia (AML) cases. To understand the contribution of the t(8;21) to AML, we transduced purified hematopoietic stem cells (HSC) with a retroviral vector that coexpressed AML1-ETO or just the AML1 portion (AML1d) of the translocation along with a green fluorescent protein reporter gene. Animals reconstituted with AML1-ETO-expressing cells exhibited many of the hematopoietic developmental abnormalities seen in the bone marrow of human patients with the t(8;21), although the animals did not develop acute leukemia. We noted a gradual increase in primitive myeloblasts that accounted for approximately 10% of bone marrow by 10 months posttransplant. Consistent with this observation was a 50-fold increase in myeloid colony-forming cells in vitro. In addition, accumulation of late stage metamyelocytes was observed in bone marrow along with an increase in immature eosinophil myelocytes that showed abnormal basophilic granulation. There was also a gradual increase in both the frequency and absolute number of AML1-ETO-expressing HSC so that by 10 months posttransplant, there were 29-fold greater HSC numbers than in transplant-matched control mice. These phenotypes were not observed in animals reconstituted with cells expressing only the DNA-binding domain of AML1, suggesting that the ETO domain is necessary to establish the developmental abnormalities associated with AML1-ETO expression in HSC.
AB - Translocation of the ETO gene on human chromosome 8 with the AML1 gene on chromosome 21 (AML1-ETO) is a recurrent cytogenetic abnormality associated with approximately 12% of acute myelogenous leukemia (AML) cases. To understand the contribution of the t(8;21) to AML, we transduced purified hematopoietic stem cells (HSC) with a retroviral vector that coexpressed AML1-ETO or just the AML1 portion (AML1d) of the translocation along with a green fluorescent protein reporter gene. Animals reconstituted with AML1-ETO-expressing cells exhibited many of the hematopoietic developmental abnormalities seen in the bone marrow of human patients with the t(8;21), although the animals did not develop acute leukemia. We noted a gradual increase in primitive myeloblasts that accounted for approximately 10% of bone marrow by 10 months posttransplant. Consistent with this observation was a 50-fold increase in myeloid colony-forming cells in vitro. In addition, accumulation of late stage metamyelocytes was observed in bone marrow along with an increase in immature eosinophil myelocytes that showed abnormal basophilic granulation. There was also a gradual increase in both the frequency and absolute number of AML1-ETO-expressing HSC so that by 10 months posttransplant, there were 29-fold greater HSC numbers than in transplant-matched control mice. These phenotypes were not observed in animals reconstituted with cells expressing only the DNA-binding domain of AML1, suggesting that the ETO domain is necessary to establish the developmental abnormalities associated with AML1-ETO expression in HSC.
KW - AML1-ETO
KW - Hematopoietic stem cell
KW - Leukemia
KW - Myeloid development
UR - http://www.scopus.com/inward/record.url?scp=0038300361&partnerID=8YFLogxK
U2 - 10.1016/S1079-9796(03)00025-1
DO - 10.1016/S1079-9796(03)00025-1
M3 - Article
C2 - 12732184
AN - SCOPUS:0038300361
VL - 30
SP - 201
EP - 206
JO - Blood Cells, Molecules, and Diseases
JF - Blood Cells, Molecules, and Diseases
SN - 1079-9796
IS - 2
ER -