Deletions and rearrangement of CDKN2 in lymphoid malignancy

Abstract

Recurrent abnormalities of the short arm of chromosome 9, including translocations and interstitial deletions, have been reported in both leukemia and lymphoma. The pathologic consequences of these abnormalities remain unknown. The cyclin-dependent kinase 4 inhibitor (CDKN2) gene, which maps to 9p21, has been implicated by the finding of a high frequency of biallelic deletions in leukemic cell lines. We have determined the incidence of structural abnormalities affecting CDKN2 by DNA blot in a panel of 231 cases of leukemia and lymphoma and 66 cell lines derived from patients with lymphoid malignancies with defined cytogenetic abnormalities. Structural alterations of CDKN2 were seen in 20 (8.3%) of all fresh cases and 10 (15.1%) of all cell lines. Biallelic CDKN2 deletions were seen in 11 of 53 (21%) cases of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There was no association with any particular cytogenetic abnormality. Biallelic deletions were also found 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 sequential samples showed loss of CDKN2 with transformation. Neither deletions nor rearrangements of the CDKN2 gene were seen in any of the 119 leukemias of mature B or T cells analyzed. Biallelic deletions of CDKN2 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 these 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 line 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 high-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, transplantable leukemia in mice with severe combined immunodeficiency (SCID), seven showed biallelic CDKN2 deletions. In contrast, none of 11 cases that failed to engraft showed biallelic CDKN2 deletions. BCP-ALL cases that lack CDKN2 expression may have a particular propensity to grow in SCID mice.

Deletion mapping indicates that MTS1 is the target of frequent deletions at chromosome 9p21 in paediatric acute lymphoblastic leukaemias

“…Taken together with the previous observation that in one patient exon 3 of MTS1 was homozygously deleted whereas one copy of exons 1 and 2 was retained (Cayuela et al, 1995), our results strongly suggest that MTS1 is the suppressor gene which is the target of deletions at 9p21 in ALLs. In agreement with previous reports, biallelic deletions of either MTS2 or interferon genes were never observed in the absence of homozygous deletion of MTS1 (Duro et al, 1994;Ogawa et al, 1994;Hebert et al, 1994;Quesnel et al, 1995;Cayuela et al, 1995;Stranks et al, 1995;Sill et al, 1995;Otsuki et al, 1995;Okuda et al, 1995). It may be surprising that inactivating intragenic mutations were never observed in the MTS1 gene, though we and others (Okuda et al, 1995) have explored this possibility extensively by sequencing.…”

“…In contrast, MTS2 has not been implicated yet in human cancer. In ALLs, several recent reports indicated a high frequency of homozygous deletions of MTS1, especially in leukaemias of the Tlineage (Duro et al, 1994;Ogawa et al, 1994;Hebert et al, 1994;Quesnel et al, 1995;Cayuela et al, 1995;Stranks et al, 1995;Sill et al, 1995;Otsuki et al, 1995;Okuda et al, 1995). In some cases abnormal restriction fragments were detected using MTS1 probes, suggesting either a partial deletion or a rearrangement of one allele of this gene, whereas the other allele was deleted.…”

Mutational and methylation analysis of the cyclin‐dependent kinase 4 inhibitor (p16INK4A) gene in chronic lymphocytic leukemia

“…Although p16 inactivation is probably a rare molecular event in low-grade B-cell non-Hodgkin's lymphoma (NHL), the published data about p16 alterations in CLL are relatively scanty (13). In most of the previous studies p16 abnormalities have been examined in non-homogenous patient population with different subtypes of B-NHL, while concurrent examination of deletions and mutations has rarely been performed in the same patient population (32)(33)(34)(35)(36)(37). In this study, we have analyzed the p16 gene structure for the presence of deletions and/or mutations in 34 cases of CLL.…”

Acute lymphoblastic leukemia a comprehensive review with emphasis on biology and therapy

“…245 However, recent studies suggest that a tumor-suppressor gene known as p16, MTS1, or CDKN2, which codes for a cyclin-dependent kinase 4 inhibitor, is more often involved in leukemias with 9p delealthough it can also affect patients without a 9p d e l e t i~n .~~~,~~~ Abnormalities in 6q occur in 6% of cases,163 and their clinical and prognostic significance is uncertain. 249 The short arm of chromosome 12 is tions, [246][247][248] CD34 expression has been correlated with a favorable outcome in children with pre-B phenotype,260 but not in Expression of multidrug resistance (MDR)associated protein P-170 has been reported to confer a poor prognosis among both children and adults.261 Patients with MDR-positive ALL at diagnosis had lower complete remission, higher relapse, and shorter survival rates than patients with MDR-negative ALL. 26 complete remission within 4 weeks from the start of therapy have a significant1;y worse prognosis than those who d0.150,'40 Furthermore, after 7-14 days of induction therapy, patients with leukemic blasts greater than or equal to 5% in bone marrow aspirate have a significantly higher incidence of relapse than do patients with less than 5%.…”