Oncogenesis of T-ALL and Nonmalignant Consequences of Overexpressing Intracellular NOTCH1

Abstract

Mutations resulting in overexpression of intracellular Notch1 (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)-\(\alpha \beta^+\) 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 posttranslational modification. The first tumorigenic cells are detected among more immature \(CD4^−8^+TCR-\alpha \beta^-\) cells that give rise to monoclonal tumors with a single, unique TCR-\(\beta\) chain and diverse TCR-\(\alpha\) chains, pinpointing malignant transformation to a stage after pre-TCR signaling and before completion of TCR-\(\alpha\) rearrangement. In T-ALL, E2A deficiency is accompanied by further transcriptional up-regulation of c-Myc and concomitant dysregulation 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 karyotype (SKY) analysis, none of the tumors arise because of genomic instability.