Synergistic up-regulation of the myeloid-specific promoter for the macrophage colony-stimulating factor receptor by AML1 and the t(8;21) fusion protein may contribute to leukemogenesis.

Rhoades KL, Hetherington CJ, Rowley JD, Hiebert SW, Nucifora G, Tenen DG, Zhang DE
Proc Natl Acad Sci U S A. 1996 93 (21): 11895-900

PMID: 8876234 · PMCID: PMC38155 · DOI:10.1073/pnas.93.21.11895

AML1 is involved in the (8;21) translocation, associated with acute myelogenous leukemia (AML)-type M2, which results in the production of the AML1-ETO fusion protein: the amino-terminal 177 amino acids of AML1 and the carboxyl-terminal 575 amino acids of ETO. The mechanism by which AML1-ETO accomplishes leukemic transformation is unknown; however, AML1-ETO interferes with AML1 transactivation of such AML1 targets as the T-cell receptor beta enhancer and the granulocyte-macrophage colony-stimulating factor promoter. Herein, we explored the effect of AML1-ETO on regulation of a myeloid-specific AML1 target, the macrophage colony-stimulating factor (M-CSF) receptor promoter. We found that AML1-ETO and AML1 work synergistically to transactivate the M-CSF receptor promoter, thus exhibiting a different activity than previously described. Truncation mutants within the ETO portion of AML1-ETO revealed the region of ETO necessary for the cooperativity between AML1 and AML1-ETO lies between amino acids 347 and 540. Endogenous M-CSF receptor expression was examined in Kasumi-1 cells, derived from a patient with AML-M2 t(8;21) and the promonocytic cell line U937. Kasumi-1 cells exhibited a significantly higher level of M-CSF receptor expression than U937 cells. Bone marrow from patients with AML-M2 t(8;21) also exhibited a higher level of expression of M-CSF receptor compared with normal controls. The upregulation of M-CSF receptor expression by AML1-ETO may contribute to the development of a leukemic state in these patients.

MeSH Terms (21)

Animals Bone Marrow Cell Line Cercopithecus aethiops Chromosomes, Human, Pair 8 Chromosomes, Human, Pair 21 Core Binding Factor Alpha 2 Subunit DNA-Binding Proteins DNA Primers Humans Leukemia, Myeloid, Acute Organ Specificity Polymerase Chain Reaction Promoter Regions, Genetic Proto-Oncogene Proteins Receptor, Macrophage Colony-Stimulating Factor RUNX1 Translocation Partner 1 Protein Transcription Factors Translocation, Genetic Tumor Cells, Cultured Up-Regulation

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