ZFIN ID: ZDB-PUB-120430-15
Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency
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.
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
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ABSTRACT

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.

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