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Inactivation of the ATM Gene in T-Cell Prolymphocytic Leukemias
- Source :
- ResearcherID, Marc-Henri Stern
- Publication Year :
- 1998
- Publisher :
- American Society of Hematology, 1998.
-
Abstract
- T-cell prolymphocytic leukemia (T-PLL) is a rare form of mature leukemia that occurs both in adults as a sporadic disease and in younger patients suffering an hereditary condition, ataxia telangiectasia (AT). The ATM gene, located in the 11q22-23 chromosomal region, is consistently mutated in AT patients. The strong predisposition of AT patients to develop T-PLL and the high frequency of T-cell leukemias/lymphomas observed in atm-deficient mice, together with the known functions of the ATM protein, led us to evaluate the ATM gene as a potential tumor suppressor gene involved in T-PLL. Paired leukemic and nonleukemic cells were obtained from a series of 15 patients suffering sporadic T-PLLs, allowing loss of heterozygosity (LOH) analysis. LOH of the 11q22-23 region was detected in 10 of these 15 cases (67%). The minimal deleted region was defined as an approximately 2.5 Mb interval that contained the ATMgene. No ATM rearrangement or biallelic deletion was detected by Southern blotting in the T-PLL series. However, in five T-PLLs with LOH of the 11q22-23 region, Western blot analysis showed either undetectable (3 cases) or decreased levels (1 case) of ATM protein, whereas ATM was present at high levels in cases without LOH. The protein truncation test (PTT) was then used to search for mutations in the ATM gene. Four mutations (1 nonsense, 2 aberrant splicings, and 1 missense) were detected in patients with LOH and none in patients without LOH of the region. The acquired character of these ATM mutations was demonstrated in three patients. Altogether, allelicATM inactivations by large deletions or mutations were found in approximately two thirds of T-PLL. ATM is thus a tumor suppressor gene whose inactivation is a key event in the development of T-cell prolymphocytic leukemias.
- Subjects :
- Adult
Tumor suppressor gene
RNA Splicing
DNA Mutational Analysis
Molecular Sequence Data
Immunology
Loss of Heterozygosity
Cell Cycle Proteins
Ataxia Telangiectasia Mutated Proteins
Biology
Protein Serine-Threonine Kinases
medicine.disease_cause
Polymerase Chain Reaction
Biochemistry
Loss of heterozygosity
Leukemia, Prolymphocytic
medicine
Humans
Genes, Tumor Suppressor
Prolymphocytic leukemia
Alleles
Cell Line, Transformed
Sequence Deletion
Mutation
Base Sequence
Chromosomes, Human, Pair 11
Tumor Suppressor Proteins
Proteins
DNA, Neoplasm
Exons
Cell Biology
Hematology
medicine.disease
Molecular biology
DNA-Binding Proteins
Leukemia
Chromosomal region
Ataxia-telangiectasia
T-cell prolymphocytic leukemia
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 91
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....474143e3d756f447b3405cece9916663