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Disruption of the Multiple Tumor Suppressor Gene MTS1/p16INK4a/CDKN2 by Illegitimate V(D)J Recombinase Activity in T-Cell Acute Lymphoblastic Leukemias
Jean-Michel Cayuela,
Betty Gardie, and
François Sigaux
From the Laboratory of Molecular Hematology, Institut National de la Santé et de la Recherche Médicale (INSERM) U462, Centre Hayem, Hôpital Saint Louis, Paris, France.
We have recently shown that the multiple tumor suppressor gene 1 (MTS1 ) encoding the p16INK4a and p19ARF cell-cycle inhibitors is inactivated by deletion or disruption in most human T-cell acute lymphoblastic leukemias (T-ALLs), representing the most frequent genetic event thus far described in this disease. To analyze the mechanism of these chromosomal events, we used cloning, sequencing, and/or polymerase chain reaction mapping to study 15 rearrangements occurring in the MTS1 locus. We found that these breakpoints occur in two clusters (MTS1bcr and MTS1bcr ). The three rearrangements occurring in MTS1bcr correspond to a recurrent recombination juxtaposing 5' MTS2 exon 1 and 5' MTS1 exon 1 sequences. Breakpoints for 10 of 12 rearrangements within MTS1bcr are located at a polymorphic (CA) repeat, suggesting that this sequence might play a role in the clustering. For both MTS1bcr and MTS1bcr, sequence analyses and PCR mapping experiments show that the tightly clustered breakpoints are located in the vicinity of heptamers whose sequence is similar to those involved in the V(D)J recombination. Moreover, short deletions, GC-rich random nucleotide additions, and clone-specific junctional sequences are present in all cases, further suggesting that the rearrangements are due to illegitimate V(D)J recombinase activity. These data are the first demonstration that a tumor suppressor gene can be inactivated by the V(D)J recombinational mechanism. Moreover, they reinforce the view that this process, normally required for T-cell differentiation, plays a crucial role in the pathogenesis of T-ALL.
Blood, Vol. 90 No. 9 (November 1), 1997:
pp. 3720-3726
© 1997 by The American Society of Hematology.
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