Inactivation of the ATM gene in T-cell prolymphocytic leukemias.
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 ATM gene. 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, allelic ATM 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.
Stoppa-Lyonnet
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D
Unité INSERM U462, Hôpital Saint Louis, Paris, France.
Soulier
J
J
Laugé
A
A
Dastot
H
H
Garand
R
R
Sigaux
F
F
Stern
M H
MH
D000328:Adult; D000483:Alleles; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D005091:Exons / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006801:Humans; D015463:Leukemia, Prolymphocytic / Q000235:genetics*; D019656:Loss of Heterozygosity; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases