Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1

Abstract

Mutations resulting in overexpression of intracellular Notchl (ICN1) are frequently observed in human T cell acute lymphoblastic leukemia (T-ALL). We have determined the consequences of ICN1 overexpression from retroviral vectors introduced into bone marrow cells. Early consequences are the generation of polyclonal nontumorigenic CD4+8+ T cell receptor (TCR)-«P+ cells that do not qualify as tumor precursors despite the observation that they overexpress Notch 1 and c-Myc and degrade the tumor suppressor E2A by post- translational modification. The first tumorigenic cells are detected among more immature CD4∼8+TCR-aP∼ cells that give rise to monoclonal tumors with a single, unique TCR-P chain and diverse TCR-a chains, pinpointing malignant transformation to a stage after pre- TCR signaling and before completion of TCR-a rearrangement. In T-ALL, E2A deficiency is accompanied by further transcriptional up-regulation of c-Myc and concomitant dysregu- lation of the c-Myc-p53 axis at the transcriptional level. Even though the tumors consist of phenotypically heterogeneous cells, no evidence for tumor stem cells was found. As judged by array-based comparative genomic hybridization (array CGH) and spectral karyo- type (SKY) analysis, none of the tumors arise because of genomic instability.