Multiple Tumor-Suppressor Gene 1 Inactivation Is the Most Frequent Genetic Alteration in T-Cell Acute Lymphoblastic Leukemia

• Published in: Blood Vol. 87; no. 6; pp. 2180 - 2186
• Main Authors: Cayuela, Jean-Michel, Madani, Ali, Sanhes, Laurence, Stern, Marc-Henri, Sigaux, François
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.03.1996; The Americain Society of Hematology
• Subjects: Adult; Alleles; Base Sequence; Biological and medical sciences; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Cell Cycle Proteins; Child; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; DNA Mutational Analysis; Exons - genetics; Female; Gene Deletion; Gene Rearrangement; Genes, Tumor Suppressor; Hematologic and hematopoietic diseases; Humans; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemia-Lymphoma, Adult T-Cell - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Molecular Sequence Data; Point Mutation; Polymorphism, Single-Stranded Conformational; Retrospective Studies; Thymus Gland - metabolism; Tumor Suppressor Proteins; Chromosomal aberration; Human; Lymphoproliferative syndrome; Acute; Point mutation; Gene rearrangement; Deletion; Abnormal chromosome; Malignant hemopathy; Acute lymphocytic leukemia; Inactivation; Tumor suppressor gene
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V87.6.2180.bloodjournal8762180

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 1α and 2 was found and MTS1 RNA was detected in the fourth case, but a rearrangement occurring 5’ to MTS1 exon 1 α deleting MTS1 exon 1β 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 1β. 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.