Abstract
Chromosomal rearrangements are implicated in the etiology of T-cell lymphomagesesis and Rag-dependent and independent pathways participate in mouse thymic lymphomagenesis. However, Rag-dependent and -independent mechanisms for the rearrangements of cancer-related genes are not well characterized. We present the molecular mechanisms for Notch1 rearrangements by comparing susceptibility of Rag2-/-, Atm-/-, scid, and doubly mutated mice to thymic lymphomagenesis and by identifying sequence specificities of the junctions of Notch1 rearrangements in thymic lymphomas. Rag2-/- mice spontaneously develop thymic lymphomas via Rag2-independent pathway. Scid mice develop radiation-induced thymic lymphomas mainly via Rag2-independent pathway. Atm-/- mice develop them via both pathways. Total abnormalities in the Notch1 including rearrangements and mutations exceed 80% in thymic lymphomas, making Notch1 the most important oncogene for thymic lymphomagenesis. Analyses of Notch1 rearrangements show that Rag2-dependent mechanisms are the illegitimate V(D)J recombination and the Rag2-mediated pathway where Rag-cleaved DNA end and another DNA break are involved. Rag2-independent mechanisms include the microhomology-mediated end-joining, the nucleotide addition in deletion, the insertion of intracisternal A particle, inversion, duplication, and translocation. These mechanisms bring about the generation of Notch1 rearrangements, depending on the defects of mutant mice in repair and V(D)J recombination, indicating that errors in V(D)J recombination and DNA repair are involved in lymphomagenesis through the formation of rearrangements.
