Evaluation of a-Catenin(CTNNA1) As a Tumor Suppressor Gene in Acute Myeloid Leukemis

Abstract 5240

Human a-catenin (CTNNA1) is a 102-kDa cadherin-binding protein that has been recognized as a tumor suppressor gene in solid tumors. Recent studies suggested that a-catenin functional as a tumor suppressor gene in leukemia with 5q deletion as well. In the present study, we speculate that a-catenin may play an important role as a tumor suppressor gene in AML and MDS cases with del(5q), since it is located on chromosome 5, band q31, and within the interval that is consistently deleted in these malignancies. Here, we report the evaluation of a-catenin as a tumor suppressor in myeloid disorders by mutational and functional analysis. Northern blot analysis revealed a very low level of expression of a-catenin mRNA in a panel of leukemia cell lines, whereas it was slightly higher in breast, colon, and prostate cancer lines. Protein truncation analysis in 11 myeloid leukemia cell lines revealed no mutations. By genomic sequencing selected exons in 23 clinical samples of AML/MDS patients with del(5q), we found that 1 of the samples carries a mismatch mutation on exon 5 of the gene. Using pcDNA-catenin expression vector for gene transfection analysis, we found that constitutive expression of a-catenin in the del(5q) leukemia cell line MUTZ-8 inhibited colony formation by 38.7%±6.3%(mea±sd) in the catenin-expressing cells when compared to those with empty vector and caused G1 arrest in the catenin-expressing cells (85.2%±7.3% vs 65.1%±4.6% in control cells) by cell cycle analysis. We conclude that a-catenin causes growth suppression in myeloid leukemia cells, which is consistent with a tumor suppressor gene, and endogenous expression of a-catenin is decreased in most of these cells; However, the finding a-catenin mutation in 1 out of 23 leukemia samples provides limited evidence that it is mutationally inactivated in human leukemias.