Inverse correlation between loss of heterozygosity of the short arm of chromosome 12 and p15^ink4B/p16^ink4 gene inactivation in childhood acute lymphoblastic leukaemia

Abstract

Summary.Seventy-four patients with acute lymphoblastic leukaemia (ALL) were analysed with limited allelotyping to detect loss of heterozygosity on chromosome segments 6q, 9p, 12p and 13q in order to detect patterns of genetic alteration. In the case of chromosome 9, analyses were also performed to detect inactivation of the p15 ink4B and p16 ink4 genes by Southern blot and sequencing techniques. The deletion data from these chromosomes were correlated to each other and to clinical features including prognosis. Allelic loss of these chromosomal regions could be detected in 24% (6q), 15% (12p) and 10% (13q) of the patients respectively, whereas aberrations involving 9p were detected in approximately 50% of the cases. There was an inverse correlation between loss of heterozygosity (LOH) for chromosome 12 and inactivation of the p16 ink4 gene. This finding may suggest that a leukaemogenic event on chromosome 12p affects the same pathway of cell-cycle control as p16 ink4 inactivation or, alternatively, reflects the fact that these mutations tend to occur in cells of different lineages.

Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia

“…[14][15][16][17] Yet, the prognostic significance of CDKN2A/B deletions remains inconclusive. Depending on the study design and the composition of the analyzed population, CDKN2A/B deletions were either of no prognostic value 14,15 or associated with poor prognostic parameters and inferior outcome.…”

Loss of heterozygosity in childhood de novo acute myelogenous leukemia

“…For example, it was noted previously that chromosome arm 12p is frequently aberrant in childhood ALL, 14,15,47 as is 13q in childhood ALL and adult chronic lymphocytic leukemia. 14,[48][49][50] Furthermore, several of the loci detected in this study were previously implicated in the pathogenesis of AML, including deletion of 9q, 51 monosomy 7, partial deletions of 7q 23,[52][53][54][55] and 5q, and abnormalities of 3q. 1,25 Our finding of LOH on 5q and 3q in 2 patients without such abnormalities on cytogenetic analysis indicates that LOH analysis may be a more sensitive technique for identifying such patients with a poor prognosis.…”

Paediatric lymphoblastic T‐cell leukaemia and lymphoma: one or two diseases?

“…Defective cell cycle surveillance mechanisms are likely to be the major factors leading to deregulated proliferation and chromosomal abnormalities that are associated with leukaemic cells. Alterations of chromosome 9p, which contains the CDKN2A/CDKN2B loci encoding for the cyclin-dependent kinase inhibitors p16 INK4A , p15 INK4B and the alternative reading frame protein of the CDKN2A locus, p14 ARF , were reported earlier for ALL in about 30-70% of the cases, with higher frequency in T-ALL compared to precursor B-ALL (Okuda et al, 1995;Heyman et al, 1997;Rubnitz et al, 1997;Takeuchi et al, 2003). The prognostic significance of CDKN2A deletions has remained inconclusive.…”