Abstract
The t(8;21)(q22;q22) is common in adult acute myeloid leukemia (AML). The RUNX1-ETO fusion protein that is expressed by this translocation is poorly leukemogenic and requires additional mutations for transformation. Loss of sex chromosome (LOS) is frequently observed in t(8;21) AML. In the present study, to evaluate whether LOS cooperates with t(8;21) in leukemogenesis, we first used a retroviral transduction/transplantation model to express RUNX1-ETO in hematopoietic cells from XO mice. The low frequency of leukemia in these mice suggests that the potentially critical gene for suppression of t(8;21) leukemia in humans is not conserved on mouse sex chromosomes. The gene encoding the GM-CSF receptor α subunit (CSF2RA) is located on X and Y chromosomes in humans but on chromosome 19 in mice. GM-CSF promotes myeloid cell survival, proliferation, and differentiation. To determine whether GM-CSF signaling affects RUNX1-ETO leukemogenesis, hematopoietic stem/progenitor cells that lack GM-CSF signaling were used to express RUNX1-ETO and transplanted into lethally irradiated mice, and a high penetrance of AML was observed in recipients. Furthermore, GM-CSF reduced the replating ability of RUNX1-ETO-expressing cells. These results suggest a possible tumor-suppressor role of GM-CSF in RUNX1-ETO leukemia. Loss of the CSF2RA gene may be a critical mutation explaining the high incidence of LOS associated with the t(8;21)(q22;q22) translocation.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adult
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Animals
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Cells, Cultured
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Chromosomes, Human, Pair 21 / genetics
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Chromosomes, Human, Pair 8 / genetics
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Chromosomes, Mammalian / genetics
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Core Binding Factor Alpha 2 Subunit / genetics
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DNA-Binding Proteins / genetics
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Granulocyte-Macrophage Colony-Stimulating Factor / genetics
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
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Granulocyte-Macrophage Colony-Stimulating Factor / physiology
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Humans
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Oncogene Proteins, Fusion / genetics
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Proto-Oncogene Proteins / genetics
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Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics
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Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
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Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / physiology
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Sex Chromosomes / genetics
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Sex Chromosomes / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Transcription Factors / genetics
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Translocation, Genetic*
Substances
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Core Binding Factor Alpha 2 Subunit
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Csf2ra protein, mouse
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DNA-Binding Proteins
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MTG8 protein, mouse
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins
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Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
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Transcription Factors
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Granulocyte-Macrophage Colony-Stimulating Factor