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Multiple tumor-suppressor gene 1 inactivation is the most frequent genetic alteration in T-cell acute lymphoblastic
J M Cayuela1, A Madani, L Sanhes
1Laboratory of Molecular Hematology, Centre Hayem, Hopital Saint Louis, Paris, France.
Abstract:
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.
Insights
Multiple tumor-suppressor gene 1 (MTS1) inactivation is the most consistent genetic defect in T-cell acute lymphoblastic leukemia (T-ALL), occurring in at least 80% of cases. This study characterized MTS1 and MTS2 gene alterations in T-ALL patients.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- T-cell acute lymphoblastic leukemia (T-ALL) lacks a constant genetic alteration.
- The SIL-TAL1 deletion is the most frequent alteration, found in ~20% of T-ALL cases.
- Multiple tumor-suppressor genes 1 (MTS1) and 2 (MTS2) inhibit cell cycle progression.
Purpose of the Study:
- To characterize the organization of the MTS locus.
- To determine the incidence of MTS1 and MTS2 inactivation in T-ALL.
- To identify the primary genetic target in T-ALL development.
Main Methods:
- Southern blotting using 8 probes to analyze MTS1 and MTS2 configurations in 59 T-ALL patients.
- Northern blot analysis to assess MTS1 mRNA expression.
- Single-strand conformation polymorphism (SSCP) to detect mutations.
Main Results:
- Biallelic MTS1 inactivation (deletions/rearrangements) observed in 76% of T-ALL cases.
- Monoallelic MTS1 alterations found in 10% of cases.
- MTS1 inactivation identified in at least 80% of T-ALL, significantly more frequent than SIL-TAL1 deletion.
Conclusions:
- MTS1 inactivation is the most consistent genetic defect identified in T-ALL to date.
- MTS1, but not MTS2, RNA is detected in human thymus, suggesting MTS1 is the functional target.
- The findings strongly implicate MTS1 as the primary genetic target of rearrangements in T-ALL.