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

172 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    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