The 8;21 translocation occurs in approximately 8% of patients with acute myeloid leukemia. This chromosomal lesion results in the fusion of the AML1 (RUNX1) gene on chromosome 21 to the ETO (MTG8) gene on chromosome 8 and generates the AML1-ETO fusion protein. We identified a truncated form of AML1-ETO which lacks approximately 200 amino acids at the C-terminus of full length AML1-ETO and strongly induces leukemia development (

Yan et al, PNAS 101(49): 17186–91, 2004
). This protein is almost identical to a natural splice form of AML1-ETO designated AML1-ETO9a, which is expressed in t(8;21) patients. To study the leukemogenic properties of the truncated form of AML1-ETO (AEtr), we examined cell cycle profiles to compare it to full length AML1-ETO. In contrast to full length AML1-ETO which induced growth arrest of K562 cells, AEtr did not inhibit cell proliferation. Interestingly, AEtr expressing cells continued to proliferate in the presence of microtubule toxins that normally activate the spindle checkpoint and arrest cells in prometaphase of mitosis. Evaluation of critical components of the spindle checkpoint revealed a significant decrease in BubR1 protein in AEtr cells compared to vector control cells. BubR1 is a potent inhibitor of the anaphase promoting complex and reduction of BubR1 by either siRNA approaches or gene deletion in mice results in aneuploidy. Cytogenetic analyses of leukemic splenocytes from mice transplanted with AEtr cells identified multiple chromosomal abnormalities, including chromosome loss and gain as well as translocations. Observations of chromosomal alterations in t(8;21) patients have been well documented and include loss of either sex chromosome in 70% of patients, deletions of chromosome 9, and trisomy 8. These results indicate that inactivation of the spindle checkpoint through BubR1 reduction may be an important event in the development of t(8;21) leukemias.

Topics:
aneuploidy, fusion proteins, spindle integrity checkpoint, leukemia, amino acids, cytogenetic analysis, leukemia, myelocytic, acute, rna, small interfering, toxins, chromosome abnormality

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2005, The American Society of Hematology
2005
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