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Role of tumor suppressor genes in the development of adult T cell leukemia/lymphoma (ATLL)

Leukemia volume 16, pages 1069–1085 (2002)Cite this article

Abstract

Adult T cell leukemia/lymphoma (ATLL) is one of the peripheral T cell malignant neoplasms strongly associated with human T cell leukemia virus type-I (HTLV-I). Although the viral transactivating protein Tax has been proposed to play a critical role in leukemogeneis as shown by its transforming activity in various experimental systems, additional cellular events are required for the development of ATLL. One of the genetic events in ATLL is inactivation of tumor suppressor genes. Among many candidates for tumor suppressor genes, the main genetic events have been reported to center around the cyclin-dependent kinase inhibitors ((CDKIs) p15INK4A, p16INK4B, p18INK4C, p19INK4D, p21WAF1, p27KIP1, and p57KIP2), p53 and Rb genes; all of them play a major regulatory role during G1 to S transition in the cell cycle. Acute/lymphomatous ATLL has frequent alterations of p15 (20%) and p16 (28–67%), while chronic/smoldering ATLL has fewer abnormalities of p15 (0–13%) and p16 (5–26%). Most of these changes are deletion of the genes; fewer samples have mutations. ATLL patients with deleted p15 and/or p16 genes have significantly shorter survival than those individuals with both genes preserved. Although genetic alterations of p18, p19, p21, p27 have rarely been reported, inactivation of these genes may contribute to the development of ATLL because low expression levels of these genes seem to mark ATLL. The p53 gene is mutated in 10–50% of acute/lymphomatous ATLL. Functional impairment of the p53 protein, even if the gene has wild-type sequences, has been suggested in HTLV-I infected cells. Each of these genetic events are mainly found in acute/lymphomatous ATLL, suggesting that alterations of these genes may be associated with transformation to an aggressive phenotype. The Rb tumor suppressor gene is infrequently structurally altered, but one half of ATLL cases have lost expression of this key protein. Notably, alterations of one of the CDKIs, p53 and Rb genes appear to obviate the need for inactivation of other genes in the same pathway. A novel tumor suppressor gene on chromosome 6q may also have a critical role in the pathogenesis of ATLL. Taken together, tumor suppressor genes are frequently altered in acute/lymphomatous ATLL and their alteration is probably the driving force fueling the transition from chronic/smoldering to acute/lymphomatous ATLL.

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Acknowledgements

We are indebted to our colleagues for continuous support and advice; to Kim Burgin and Marge Jacobs (posthumously) for their excellent secretarial help. Supported in part by the NIH grants, the Ko-So Foundation, Lymphoma Foundation of America, The Begell Foundation and the C and H Koeffler fund. HP Koeffler holds the endowed Mark Goodson Chair of Oncology research at Cedars-Sinai Medical Center/UCLA School of Medicine and is a member of the Jonsson Cancer Center.

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  1. First Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan

    Y Hatta

  2. Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA

    HP Koeffler

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Hatta, Y., Koeffler, H. Role of tumor suppressor genes in the development of adult T cell leukemia/lymphoma (ATLL). Leukemia 16, 1069–1085 (2002). https://doi.org/10.1038/sj.leu.2402458

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