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Multiple tumor-suppressor gene 1 inactivation is the most frequent genetic
alteration in T-cell acute lymphoblastic leukemia
JM Cayuela, A Madani, L Sanhes, MH Stern and F Sigaux
Laboratory of Molecular Hematology, Centre Hayem, Hopital Saint Louis,
Paris, France.
No constant genetic alteration has yet been unravelled in T-cell acute
lymphoblastic leukemia (T-ALL), and, to date, the most frequent alteration,
the SIL-TAL1 deletion, is found in approximately 20% of cases. Recently,
two genes have been identified, the multiple tumor- suppressor gene 1
(MTS1) and multiple tumor-suppressor gene 2 (MTS2), whose products inhibit
cell cycle progression. A characterization of the MTS locus organization
allowed to determine the incidence of MTS1 and MTS2 inactivation in T-ALL.
MTS1 and MTS2 configurations were determined by Southern blotting using 8
probes in 59 patients with T- ALL (40 children and 19 adults). Biallelic
MTS1 inactivation by deletions and/or rearrangements was observed in 45
cases (76%). Monoallelic alterations were found in 6 cases (10%). The
second MTS1 allele was studied in the 4 cases with available material. A
point mutation was found in 2 cases. The lack of MTS1 mRNA expression was
observed by Northern blot analysis in a third case. A normal single- strand
conformation polymorphism pattern of MTS1 exons 1alpha and 2 was found and
MTS1 RNA was detected in the fourth case, but a rearrangement occurring 5'
to MTS1 exon 1 alpha deleting MTS1 exon 1Beta was documented. One case
presented a complex rearrangement. Germline configuration for MTS1 and MTS2
was found in only 7 cases. The localization of the 17 breakpoints occurring
in the MTS locus were determined. Ten of them (59%) are clustered in a 6-kb
region located 5 kb downstream to the newly identified MTS1 exon 1Beta. No
rearrangement disrupting MTS2 was detected and more rearrangements spared
MTS2 than MTS1 (P<.01). MTS1 but not MTS2 RNA was detected by Northern
blotting in the human thymus. These data strongly suggest that MTS1 is the
functional target of rearrangements in T-ALL. MTS1 inactivation, observed
in at least 80% of T-ALL, is the most consistent genetic defect found in
this disease to date.
Volume 87,
Issue 6,
pp. 2180-2186,
03/15/1996
Copyright © 1996 by The American Society of Hematology
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