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Acquisition of p16(INK4A) and p15(INK4B) gene abnormalities between initial diagnosis and relapse in children with acute lymphoblastic leukemia.
- Source :
-
Blood [Blood] 1999 Apr 01; Vol. 93 (7), pp. 2380-5. - Publication Year :
- 1999
-
Abstract
- Although numerous somatic mutations that contribute to the pathogenesis of childhood acute lymphoblastic leukemia (ALL) have been identified, no specific cytogenetic or molecular abnormalities are known to be consistently associated with relapse. The p16(INK4A) (p16), which encodes for both p16(INK4A) and p19(ARF) proteins, and p15(INK4B) (p15) genes are inactivated by homozygous deletion and/or p15 promoter hypermethylation in a significant proportion of cases of childhood ALL at the time of initial diagnosis. To determine whether alterations in these genes play a role in disease progression, we analyzed a panel of 18 matched specimen pairs collected from children with ALL at the time of initial diagnosis and first bone marrow relapse for homozygous p16 and/or p15 deletions or p15 promoter hypermethylation. Four sample pairs contained homozygous p16 and p15 deletions at both diagnosis and relapse. Among the 14 pairs that were p16/p15 germline at diagnosis, three ALLs developed homozygous deletions of both p16 and p15, and two developed homozygous p16 deletions and retained p15 germline status at relapse. In two patients, p15 promoter hypermethylation developed in the interval between initial diagnosis and relapse. In total, homozygous p16 deletions were present in nine of 18 cases, homozygous p15 deletions in seven of 18 cases, and p15 promoter hypermethylation in two of eight cases at relapse. These findings indicate that loss of function of proteins encoded by p16 and/or p15 plays an important role in the biology of relapsed childhood ALL, and is associated with disease progression in a subset of cases.
- Subjects :
- Carrier Proteins physiology
Child
Child, Preschool
Cyclin-Dependent Kinase Inhibitor p15
Cyclin-Dependent Kinase Inhibitor p16 deficiency
Cyclin-Dependent Kinase Inhibitor p16 physiology
DNA Methylation
Disease Progression
Female
Gene Expression Regulation, Leukemic
Humans
Infant
Karyotyping
Loss of Heterozygosity
Male
Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis
Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
Promoter Regions, Genetic
Recurrence
Sequence Deletion
Carrier Proteins genetics
Cell Cycle Proteins
Genes, Tumor Suppressor
Genes, p16
Mutagenesis
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Tumor Suppressor Proteins
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 93
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 10090949