Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1.
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)-alphabeta(+) 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-alphabeta(-) 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.
Li
Xiaoyu
X
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Gounari
Fotini
F
Protopopov
Alexei
A
Khazaie
Khashayarsha
K
von Boehmer
Harald
H
D000328:Adult; D000818:Animals; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D020869:Gene Expression Profiling; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D016259:Genes, myc; D005822:Genetic Vectors; D042822:Genomic Instability; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007621:Karyotyping; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C497762:Notch1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016159:Tumor Suppressor Protein p53