Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency
- Authors
- Blackburn, J.S., Liu, S., Raiser, D.M., Martinez, S.A., Feng, H., Meeker, N.D., Gentry, J., Neuberg, D., Look, A.T., Ramaswamy, S., Bernards, A., Trede, N.S., and Langenau, D.M.
- ID
- ZDB-PUB-120430-15
- Date
- 2012
- Source
- Leukemia 26(9): 2069-2078 (Journal)
- Registered Authors
- Feng, Hui, Langenau, David, Look, A. Thomas, Trede, Nick
- Keywords
- thymocyte, relapse, Myc, zebrafish, self-renewal
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Blotting, Western
- Cell Line, Tumor
- Cell Proliferation
- Cell Transformation, Neoplastic*
- Gene Expression Profiling
- Gene Expression Regulation, Leukemic*
- Humans
- Mice
- Oligonucleotide Array Sequence Analysis
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology*
- Proto-Oncogene Proteins c-myc/metabolism*
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Receptor, Notch1/physiology*
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
- Thymocytes
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 22538478 Full text @ Leukemia
NOTCH1 pathway activation contributes to the pathogenesis of over 60% of T-cell acute lymphoblastic leukemia (T-ALL). While Notch is thought to exert the majority of its effects through transcriptional activation of Myc, it also likely has independent roles in T-ALL malignancy. Here, we utilized a zebrafish transgenic model of T-ALL, where Notch does not induce Myc transcription, to identify a novel Notch gene expression signature that is also found in human T-ALL and is regulated independently of Myc. Cross-species microarray comparisons between zebrafish and mammalian disease identified a common T-ALL gene signature, suggesting that conserved genetic pathways underlie T-ALL development. Functionally, Notch expression induced a significant expansion of pre-leukemic clones; however, a majority of these clones were not fully transformed and could not induce leukemia when transplanted into recipient animals. Limiting-dilution cell transplantation revealed that Notch signaling does not increase the overall frequency of leukemia-propagating cells (LPCs), either alone or in collaboration with Myc. Taken together, these data indicate that a primary role of Notch signaling in T-ALL is to expand a population of pre-malignant thymocytes, of which a subset acquire the necessary mutations to become fully transformed LPCs.