Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency

J. S. Blackburn, S. Liu, D. M. Raiser, S. A. Martinez, H. Feng, N. D. Meeker, J. Gentry, D. Neuberg, A. T. Look, S. Ramaswamy, A. Bernards, N. S. Trede, D. M. Langenau

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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.

Original languageEnglish
Pages (from-to)2069-2078
Number of pages10
JournalLeukemia
Volume26
Issue number9
DOIs
StatePublished - Sep 2012

Bibliographical note

Funding Information:
We thank Dr Ravi Mylvaganam for expert advice and assistance with cell sorting, Eric Stone and Marcellino Pena for excellent animal husbandry, and Dr Finola Moore and Tommy Jones help with data interpretation and critical review of the manuscript. JSB is supported by NIH 5T32CA09126-26. DML is supported by an American Cancer Society Research Scholar Grant, the Leukemia Research Foundation, the Alex Lemonade Stand Foundation, the Harvard Stem Cell Institute, and NIH K01AR05562190.

Keywords

  • Myc
  • relapse
  • self-renewal
  • thymocyte
  • zebrafish

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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