A carboxy-terminal deletion mutant of Notch1 accelerates lymphoid oncogenesis in E2A-PBX1 transgenic mice.
PBX1 is a proto-oncogene that plays important roles in pattern formation during development. It was discovered as a fusion with the E2A gene after chromosomal translocations in a subset of acute leukemias. The resulting E2a-Pbx1 chimeric proteins display potent oncogenic properties that appear to require dimerization with Hox DNA binding partners. To define molecular pathways that may be impacted by E2a-Pbx1, a genetic screen consisting of neonatal retroviral infection was used to identify genes that accelerate development of T-cell tumors in E2A-PBX1 transgenic mice. Retroviral insertions in the Notch1 gene were observed in 88% of tumors arising with a shortened latency. Among these, approximately half created a Notch(IC) allele, encoding the intracellular, signaling portion of Notch1, suggesting a synergistic interaction between the Notch and E2a-Pbx1 pathways in oncogenesis. The remaining proviral insertions involving Notch1 occurred in a more 3' exon, resulting in truncating mutations that deleted the carboxy-terminal region of Notch1 containing negative regulatory sequences (Notch1(DeltaC)). In contrast to Notch(IC), forced expression of Notch1(DeltaC) in transgenic mice did not perturb thymocyte growth or differentiation. However, mice transgenic for both the E2A-PBX1 and Notch1(DeltaC) genes displayed a substantially shortened latency for tumor development compared with E2A-PBX1 single transgenic mice. These studies reveal a novel mechanism for oncogenic activation of Notch1 and demonstrate a collaborative relationship between 2 cellular oncogenes that also contribute to cell fate determination during embryonic development. (Blood. 2000;96:1906-1913)
Feldman
B J
BJ
Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.
Hampton
T
T
Cleary
M L
ML
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000235:genetics; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012192:Retroviridae Infections / Q000150:complications / Q000821:virology; D016019:Survival Analysis; D013953:Thymus Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors
D018398:Homeodomain Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D015514:Oncogene Proteins, Fusion; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C089847:E2A-Pbx1 fusion protein