Hematopoietic stem cell expansion and distinct myeloid developmental abnormalities in a murine model of the AML1-ETO translocation.

de Guzman CG, Warren AJ, Zhang Z, Gartland L, Erickson P, Drabkin H, Hiebert SW, Klug CA
Mol Cell Biol. 2002 22 (15): 5506-17

PMID: 12101243 · PMCID: PMC133929 · DOI:10.1128/mcb.22.15.5506-5517.2002

The t(8;21)(q22;q22) translocation, which fuses the ETO gene on human chromosome 8 with the AML1 gene on chromosome 21 (AML1-ETO), is one of the most frequent cytogenetic abnormalities associated with acute myelogenous leukemia (AML). It is seen in approximately 12 to 15% of AML cases and is present in about 40% of AML cases with a French-American-British classified M2 phenotype. We have generated a murine model of the t(8;21) translocation by retroviral expression of AML1-ETO in purified hematopoietic stem cells (HSC). Animals reconstituted with AML1-ETO-expressing cells recapitulate the hematopoietic developmental abnormalities seen in the bone marrow of human patients with the t(8;21) translocation. Primitive myeloblasts were increased to 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. Accumulation of late-stage metamyelocytes was also observed in bone marrow along with an increase in immature eosinophilic myelocytes that showed abnormal basophilic granulation. HSC numbers in the bone marrow of 10-month-posttransplant animals were 29-fold greater than in transplant-matched control mice, suggesting that AML1-ETO expression overrides the normal genetic control of HSC pool size. In summary, AMLI-ETO-expressing animals recapitulate many (and perhaps all) of the developmental abnormalities seen in human patients with the t(8;21) translocation, although the animals do not develop leukemia or disseminated disease in peripheral tissues like the liver or spleen. This suggests that the principal contribution of AML1-ETO to acute myeloid leukemia is the inhibition of multiple developmental pathways.

MeSH Terms (23)

Acute Disease Animals Bone Marrow Cells Cell Differentiation Cell Lineage Cells, Cultured Chronic Disease Core Binding Factor Alpha 2 Subunit Disease Models, Animal Disease Progression Hematopoietic Stem Cells Hematopoietic Stem Cell Transplantation Humans Leukemia, Myeloid Leukopoiesis Mice Mice, Inbred C57BL Myeloid Cells Oncogene Proteins, Fusion RUNX1 Translocation Partner 1 Protein Transcription Factors Transduction, Genetic Translocation, Genetic

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