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Ataxia-telangiectasia and T-Cell Leukemias: No Evidence for Somatic ATM Mutation in Sporadic T-ALL or for Hypermethylation of the ATM-NPAT/E14 Bidirectional Promoter in T-PLL¹

Liping Luo, Feng-min Lu, Steve Hart, Letizia Foroni, Hodjattallah Rabbani, Lennart Hammarström, A. David B. Webster and Igor Voechovsk²

Karolinska Institute, Department of Biosciences at NOVUM, S-14157 Huddinge, Sweden [L. L., F-M. L., H. R., L. H., I. V.], and Royal Free Hospital School of Medicine, University of London, London NW3 2PF, United Kingdom [S. H., L. F., A. D. B. W., I. V.]

The ATM gene deficient in ataxia-telangiectasia, a recessive multisystem disease associated with a high risk of lymphomas and leukemias, was found previously to be inactivated in a rare sporadic malignancy, T-cell prolymphocytic leukemia (T-PLL), which is often associated with cytogenetic aberrations of chromosome 14. The ATM gene was shown to sustain frequent loss-of-function mutations in T-PLL tumor cells, consistent with functioning as a tumor suppressor gene in this leukemia. To investigate the possibility of nonmutational or nonrecombinational mechanisms of T-PLL development, we have used bisulfite genomic sequencing to analyze DNA methylation in the putative bidirectional promoter region of the closely linked ATM and NPAT/E14 genes within the CpG island at 11q22–q23. We show that this region is completely demethylated in lymphocytes expressing ATM; however, no extensive hypermethylation was found in 9 T-PLL tumor DNA samples without evidence of ATM/p53 mutations. Because acute T-cell lymphoblastic leukemias (T-ALL) were also observed in ataxia-telangiectasia patients and T-ALL tumor cells contain chromosome 14 abnormalities, 19 presentation samples of T-ALL patients were analyzed for ATM mutations. Although T-ALL patients exhibited rare nucleotide substitutions not previously found in ATM, all were identified in the germ-line, indicating constitutional polymorphisms, potentially confined to ethnic subpopulations. The absence of somatic nucleotide changes in ATM in T-ALL as compared with T-PLL suggests a distinct pattern of genetic events in the development of the two leukemias.

¹ Supported by the British Medical Research Council, the Swedish Cancer Foundation, and the European Community BIOMED Programme PL950914.

² To whom requests for reprints should be addressed, at Karolinska Institute, CBT, Blickagangen 6, 14157 Huddinge, Sweden. Phone: 46-8-6089269; Fax: 46-8-7745538; E-mail: igor.vorechovsky@cbt.ki.se.

Received 2/12/98. Accepted 4/ 9/98.

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