Abstract
The acute myelogenous leukemia-1 (AML1)-ETO fusion protein is generated by the t(8;21), which is found in 40% of AMLs of the French-American-British M2 subtype. AML1-ETO interferes with the function of the AML1 (RUNX1, CBFA2) transcription factor in a dominant-negative fashion and represses transcription by binding its consensus DNA-binding site and via protein-protein interactions with other transcription factors. AML1 activity is critical for the development of definitive hematopoiesis, and haplo insufficiency of AML1 has been linked to a propensity to develop AML. Murine experiments suggest that AML1-ETO expression may not be sufficient for leukemo genesis; however, like the BCR-ABL isoforms, the cellular background in which these fusion proteins are expressed may be critical to the phenotype observed. Retroviral gene transfer was used to examine the effect of AML1-ETO on the in vitro behavior of human hematopoietic stem and progenitor cells. Following transduction of CD34+ cells, stem and progenitor cells were quantified in clonogenic assays, cytokine-driven expansion cultures, and long-term stromal cocultures. Expression of AML1-ETO inhibited colony formation by committed progenitors, but enhanced the growth of stem cells (cobblestone area-forming cells), resulting in a profound survival advantage of transduced over nontransduced cells. AML1-ETO-expressing cells retained progenitor activity and continued to express CD34 throughout the 5-week long-term culture. Thus, AML1-ETO enhances the self-renewal of pluripotent stemcells, the physiological target of many acute myeloid leukemias.
| Original language | English |
|---|---|
| Pages (from-to) | 15-23 |
| Number of pages | 9 |
| Journal | Blood |
| Volume | 99 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2002 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Hematology
Cite this
The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells. / Mulloy, James C.; Cammenga, Jörg; MacKenzie, Karen L.; Berguido, Francisco J.; Moore, Malcolm A S; Nimer, Stephen D.
In: Blood, Vol. 99, No. 1, 01.01.2002, p. 15-23.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells
AU - Mulloy, James C.
AU - Cammenga, Jörg
AU - MacKenzie, Karen L.
AU - Berguido, Francisco J.
AU - Moore, Malcolm A S
AU - Nimer, Stephen D
PY - 2002/1/1
Y1 - 2002/1/1
N2 - The acute myelogenous leukemia-1 (AML1)-ETO fusion protein is generated by the t(8;21), which is found in 40% of AMLs of the French-American-British M2 subtype. AML1-ETO interferes with the function of the AML1 (RUNX1, CBFA2) transcription factor in a dominant-negative fashion and represses transcription by binding its consensus DNA-binding site and via protein-protein interactions with other transcription factors. AML1 activity is critical for the development of definitive hematopoiesis, and haplo insufficiency of AML1 has been linked to a propensity to develop AML. Murine experiments suggest that AML1-ETO expression may not be sufficient for leukemo genesis; however, like the BCR-ABL isoforms, the cellular background in which these fusion proteins are expressed may be critical to the phenotype observed. Retroviral gene transfer was used to examine the effect of AML1-ETO on the in vitro behavior of human hematopoietic stem and progenitor cells. Following transduction of CD34+ cells, stem and progenitor cells were quantified in clonogenic assays, cytokine-driven expansion cultures, and long-term stromal cocultures. Expression of AML1-ETO inhibited colony formation by committed progenitors, but enhanced the growth of stem cells (cobblestone area-forming cells), resulting in a profound survival advantage of transduced over nontransduced cells. AML1-ETO-expressing cells retained progenitor activity and continued to express CD34 throughout the 5-week long-term culture. Thus, AML1-ETO enhances the self-renewal of pluripotent stemcells, the physiological target of many acute myeloid leukemias.
AB - The acute myelogenous leukemia-1 (AML1)-ETO fusion protein is generated by the t(8;21), which is found in 40% of AMLs of the French-American-British M2 subtype. AML1-ETO interferes with the function of the AML1 (RUNX1, CBFA2) transcription factor in a dominant-negative fashion and represses transcription by binding its consensus DNA-binding site and via protein-protein interactions with other transcription factors. AML1 activity is critical for the development of definitive hematopoiesis, and haplo insufficiency of AML1 has been linked to a propensity to develop AML. Murine experiments suggest that AML1-ETO expression may not be sufficient for leukemo genesis; however, like the BCR-ABL isoforms, the cellular background in which these fusion proteins are expressed may be critical to the phenotype observed. Retroviral gene transfer was used to examine the effect of AML1-ETO on the in vitro behavior of human hematopoietic stem and progenitor cells. Following transduction of CD34+ cells, stem and progenitor cells were quantified in clonogenic assays, cytokine-driven expansion cultures, and long-term stromal cocultures. Expression of AML1-ETO inhibited colony formation by committed progenitors, but enhanced the growth of stem cells (cobblestone area-forming cells), resulting in a profound survival advantage of transduced over nontransduced cells. AML1-ETO-expressing cells retained progenitor activity and continued to express CD34 throughout the 5-week long-term culture. Thus, AML1-ETO enhances the self-renewal of pluripotent stemcells, the physiological target of many acute myeloid leukemias.
UR - http://www.scopus.com/inward/record.url?scp=0036095217&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036095217&partnerID=8YFLogxK
U2 - 10.1182/blood.V99.1.15
DO - 10.1182/blood.V99.1.15
M3 - Article
C2 - 11756147
AN - SCOPUS:0036095217
VL - 99
SP - 15
EP - 23
JO - Blood
JF - Blood
SN - 0006-4971
IS - 1
ER -