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Deletions and rearrangement of CDKN2 in lymphoid malignancy
G Stranks, SE Height, P Mitchell, D Jadayel, MA Yuille, C De Lord, RD Clutterbuck, JG Treleaven, RL Powles and E Nacheva
Department of Haematology and Cytogenetics, Institute of Cancer
Research-Royal Marsden Hospital, Haddow Laboratories, Sutton, Surrey, UK.
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.
Volume 85,
Issue 4,
pp. 893-901,
02/15/1995
Copyright © 1995 by The American Society of Hematology
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