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Inactivation of the ATM Gene in T-Cell Prolymphocytic
Leukemias
Dominique Stoppa-Lyonnet,
Jean Soulier,
Anthony Laugé,
Hélène Dastot,
Richard Garand,
François Sigaux, and
Marc-Henri Stern
From the Unité INSERM U462, Hôpital Saint Louis, Paris,
France; Unité de Génétique Oncologique, Institut
Curie, Paris, France; and the Laboratoire d'Hématologie, Nantes,
France; for the Groupe Français d'Hématologie Cellulaire.
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.
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3920-3926
© 1998 by The American Society of Hematology.
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