DELETIONS AND REARRANGEMENT OF CDKN2 IN LYMPHOID MALIGNANCY

Recurrent abnormalities of the short arm of chromosome 9, including tr anslocations and interstitial deletions, have been reported in both le ukemia and lymphoma. The pathologic consequences of these abnormalitie s remain unknown. The cyclin-dependent kinase 4 inhibitor (CDKN2) gene , which maps to 9p21, has been implicated by the finding of a high fre quency of biallelic deletions in leukemic cell lines. We have determin ed the incidence of structural abnormalities affecting CDKN2 by DNA bl ot in a panel of 231 cases of leukemia and lymphoma and 66 cell lines derived from patients with lymphoid malignancies with defined cytogene tic abnormalities. Structural alterations of CDKN2 were seen in 20 (8. 3%) of all fresh cases and 10 (15.1%) of all cell lines. Biallelic CDK N2 deletions were seen in 11 of 53 (21%) cases of B-cell precursor acu te lymphoblastic leukemia (BCP-ALL). There was no association with any particular cytogenetic abnormality. Biallelic deletions were also fou nd in high-grade and transformed non-Hodgkin's lymphoma (NHL) of both B- and T-cell lineages. In two cases of transformed NHL, analysis of s equential samples showed loss of CDKN2 with transformation. Neither de letions nor rearrangements of the CDKN2 gene were seen in any of the 1 19 leukemias of mature B or T cells analyzed. Biallelic deletions of C DKN2 were observed in 6 of 13 NHL cell lines. Three of the 6 cases had undergone transformation from low- to high-grade disease: in 2 of the se cases it was possible to show that the CDKN2 deletions were present in fresh material from the patient and were therefore not an artifact of in vitro culture. Rearrangements of CDKN2 were seen in 2 cases (4% ) of BCP-ALL, in 1 case of B-NHL, and in 1 Burkitt's lymphoma cell lin e and suggest the presence of a ''hot spot'' for recombination in the vicinity of the CDKN2 gene. These data indicate that the loss of CDKN2 expression may be involved in the pathogenesis of a subset of BCP-ALL , some high-grade NHL, and in the transformation of NHL from low- to h igh-grade disease. CDKN2 deletions and rearrangements occurred in the absence of detectable cytogenetic changes of chromosome 9p in 25 of 30 (83%) cases. Finally, of 10 cases of BCP-ALL that produced overt, tra nsplantable leukemia in mice with severe combined immunodeficiency (SC ID), seven showed biallelic CDKN2 deletions. In contrast, none of 11 c ases that failed to engraft showed biallelic CDKN2 deletions. BCP-ALL cases that lack CDKN2 expression may have a particular propensity to g row in SCID mice. (C) 1995 by The American Society of Hematology.