The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells

James C. Mulloy, Jörg Cammenga, Karen L. MacKenzie, Francisco J. Berguido, Malcolm A S Moore, Stephen D Nimer

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)15-23
Number of pages9
JournalBlood
Volume99
Issue number1
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

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Hematopoietic Stem Cells
Stem cells
Acute Myeloid Leukemia
Fusion reactions
Proteins
Transcription Factors
Gene transfer
Stem Cells
Transcription
Assays
Protein Isoforms
Binding Sites
Cytokines
DNA
Hematopoiesis
Experiments
Coculture Techniques
Phenotype
Survival

ASJC Scopus subject areas

  • Hematology

Cite this

Mulloy, J. C., Cammenga, J., MacKenzie, K. L., Berguido, F. J., Moore, M. A. S., & Nimer, S. D. (2002). The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells. Blood, 99(1), 15-23. https://doi.org/10.1182/blood.V99.1.15

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 journalArticle

Mulloy, JC, Cammenga, J, MacKenzie, KL, Berguido, FJ, Moore, MAS & Nimer, SD 2002, 'The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells', Blood, vol. 99, no. 1, pp. 15-23. https://doi.org/10.1182/blood.V99.1.15
Mulloy, James C. ; Cammenga, Jörg ; MacKenzie, Karen L. ; Berguido, Francisco J. ; Moore, Malcolm A S ; Nimer, Stephen D. / The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells. In: Blood. 2002 ; Vol. 99, No. 1. pp. 15-23.
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