Notch1 inhibition targets the leukemia-initiating cells in a Tal1/Lmo2 mouse model of T-ALL
Authors
Tatarek, JessicaCullion, Kathleen J.
Ashworth, Todd
Gerstein, Rachel M.
Aster, Jon C.
Kelliher, Michelle A.
UMass Chan Affiliations
Department of Molecular Genetics and MicrobiologyDepartment of Cancer Biology
Document Type
Journal ArticlePublication Date
2011-08-11Keywords
Adaptor Proteins, Signal TransducingAmyloid Precursor Protein Secretases
Animals
Basic Helix-Loop-Helix Transcription Factors
Cell Proliferation
Cells, Cultured
DNA-Binding Proteins
Disease Models, Animal
Enzyme Inhibitors
Female
Flow Cytometry
Green Fluorescent Proteins
Humans
Immunophenotyping
Kaplan-Meier Estimate
LIM Domain Proteins
Male
Metalloproteins
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Transgenic
Mutation
Neoplasm Transplantation
Neoplastic Stem Cells
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Proto-Oncogene Proteins
Receptor, Notch1
Thymus Gland
Life Sciences
Medicine and Health Sciences
Women's Studies
Metadata
Show full item recordAbstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy largely caused by aberrant activation of the TAL1/SCL, LMO1/2, and NOTCH1 oncogenes. Approximately 30% of T-ALL patients relapse, and evidence is emerging that relapse may result from a failure to eliminate leukemia-initiating cells (LICs). Thymic expression of the Tal1 and Lmo2 oncogenes in mice results in rapid development of T-ALL; and similar to T-ALL patients, more than half the leukemic mice develop spontaneous mutations in Notch1. Using this mouse model, we demonstrate that mouse T-ALLs are immunophenotypically and functionally heterogeneous with approximately 1 of 10,000 leukemic cells capable of initiating disease on transplantation. Our preleukemic studies reveal expansion of Notch-active double-negative thymic progenitors, and we find the leukemic DN3 population enriched in disease potential. To examine the role of Notch1 in LIC function, we measured LIC activity in leukemic mice treated with vehicle or with a gamma-secretase inhibitor. In 4 of 5 leukemias examined, Notch inhibition significantly reduced or eliminated LICs and extended survival. Remarkably, in 2 mice, gamma-secretase inhibitor treatment reduced LIC frequency below the limits of detection of this assay, and all transplanted mice failed to develop disease. These data support the continued development of Notch1 therapeutics as antileukemia agents.Source
Blood. 2011 Aug 11;118(6):1579-90. Epub 2011 Jun 13. Link to article on publisher's site
DOI
10.1182/blood-2010-08-300343Permanent Link to this Item
http://hdl.handle.net/20.500.14038/50981PubMed ID
21670468Related Resources
ae974a485f413a2113503eed53cd6c53
10.1182/blood-2010-08-300343
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