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

Abstract

Recent reports have indicated a high frequency of deletions of MTS1 (CDKN2, p16ink4, CDKI4) in acute lymphoblastic leukaemias (ALLs). This gene is located at chromosome 9p21 and encodes an inhibitor of cyclin D-dependent kinases. In contrast with the observations in some other malignancies, no inactivation of MTS1 by intragenic mutation was demonstrated in leukaemias. A contribution of MTS1 alterations to leukaemogenesis therefore remains questionable. In order to test for the implication of MTS1 as a tumour suppressor gene in paediatric ALLs we have explored the 9p21 chromosomal region of 46 children with this disease. The copy number of the MTS1 gene in blasts from the patients was determined using a quantitative PCR assay enabling us to precisely detect mono- and bi-allelic deletions. Rearrangements of the gene were sought by Southern blot analysis. The extent of the deletions was studied using microsatellite markers spanning the 9p21 chromosomal region. Point mutations were sought in exon 1 and exon 2 of the MTS1 gene in patients with a mono-allelic deletion in addition, exon 2 of MTS1, which contains two-thirds of the coding region, was sequenced in all patients who had no deletion of the gene. Altogether, our data are consistent with the view that MTS1 is the target of 9p21 deletions. Either one or two alleles of the gene were deleted in 36% of non-selected children with B-lineage ALL and both alleles were deleted in all seven patients we studied with T-lineage ALL. The absence of any point mutation implies that the major mechanism of inactivation of MTS1 in ALLs is deletional.

High-resolution allelotype analysis of childhood B-lineage acute lymphoblastic leukemia

“…4 Not surprisingly, the most frequent LOH are detected by markers mapped to chromosomal arms 9p and 12p in proximity to the frequently deleted MTS1 and ETV6 genes, respectively. 6,16 Detailed results of LOH results are given for the three additional regions identified in the present study: 5p, 10p, and 20q ( Figure 2).…”

“…[6][7][8] Correspondence: B Grandchamp, INSERM U409, Faculté de Méde-cine Bichat, BP 416, 75870 Paris cedex 18, France; Fax: 01 42 26 46 24 Received 15 January 1998; accepted 17 March 1998 Furthermore, the LOH approach has permitted delineation of a 6 cM interval in the 6q21-22 chromosomal band that is deleted in 7% of childhood ALL. 9 Genome-wide LOH scan or allelotype analysis of tumor DNA was first performed for colorectal cancer.…”

FISH analysis of translocations involving the short arm of chromosome 9 in lymphoid malignancies

“…In ALL patients with del(9)(p21), hemizygous or homozygous CDKN2 deletion is the rule. However, little attention has been paid to date to translocations involving 9p21, even if such cases were included in a few reports in which molecular and cytogenetic data were compared (Duro et al, 1994;Ogawa et al, 1994Ogawa et al, , 1995Delmer et al, 1995;Schrö der et al, 1995;Faienza et al, 1996;Guidal-Giroux et al, 1996;Hangaishi et al, 1996). Recently, FISH has made it possible to detect loss of the chromosomal region surrounding the CDKN2 locus by hybridization to metaphase cells and interphase nuclei using YAC probes in patients with lymphoid malignancies.…”

CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono‐ and bi‐allelic 9p21 deletions in childhood acute lymphoblastic leukemia

“…In 44 patients, results obtained for CDKN2A exon 3 were compared with those of a previously described competitive PCR method, based on the use of internal competitors (Guidal-Giroux et al, 1996). Results obtained with each method were highly correlated, with a correlation coefficient of 0.87 (Fig.…”