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ATM Mutations in B-Cell Chronic Lymphocytic Leukemia

Kimmel Cancer Institute and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [F. B., D. R., C. M. C.]; The Burnham Institute, Cancer Research Center, La Jolla, California 92037 [S. K., J. C. R.]; Section of Hematopathology, Division of Laboratory Medicine [P. S., M. A.], and Section of Leukemia, Division of Medicine [M. K.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; and Division of Hematology/Oncology, University of California San Diego, School of Medicine, La Jolla, California 92093 [T. K.]

Mutations in the ATM gene located on the long arm of chromosome 11 at 11q22–23 cause ataxia-telangiectasia, an autosomal recessive disorder that is associated with increased incidence of malignancy and, particularly, lymphoid tumors. A role for ATM in the development of sporadic T-cell chronic leukemias is supported by the finding of loss of heterozygosity at 11q22–23 and ATM mutations in leukemias carrying TCL-1 rearrangements. Approximately 14% of B-cell chronic lymphocytic leukemia (B-CLL), the most common adult leukemia, carry deletions of the long arm of chromosome 11 at 11q22–23. Loss of heterozygosity at 11q22–23 and, more recently, absence of ATM protein, have been associated with poor prognosis in B-CLL. To determine whether the ATM gene is altered in B-CLL, we have sequenced individual ATM exons in six B-CLL cases. We show that the ATM gene is mutated in a fraction of B-CLLs and that mutations can be present in the germ line of patients, suggesting that ATM heterozygotes may be predisposed to B-CLL.

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