Abstract
Notch receptors are conserved regulators of cell fate and have been implicated in the regulation of T cell differentiation and lymphomagenesis. However, neither the generality of Notch involvement in leukemia, nor the molecules with which Notch may interact have been clarified. Recently, we showed that transgenic mice expressing the constitutively active intracellular domain of Notch3 in thymocytes and T cells developed early and aggressive T cell neoplasias. Although primarily splenic, the tumors sustained features of immature thymocytes, including expression of pTalpha, a defining component of the pre T cell receptor, known to be a potent signaling complex provoking thymocyte survival, proliferation, and activation. Thus, enforced expression of Notch3, which is ordinarily down-regulated as thymocytes mature, may sustain pre T cell receptor expression, causing dysregulated hyperplasia. This hypothesis has been successfully tested in this article by the observation that deletion of pTalpha in Notch3 transgenic mice abrogates tumor development, indicating a crucial role for pTalpha in T cell leukemogenesis. Parallel observations were made in humans, in that all T cell acute lymphoblastic leukemias examined showed expression of Notch3 and of the Notch target gene HES-1, as well as of pTalpha a and b transcripts, whereas the expression of all these genes was dramatically reduced or absent in remission. Together, these results suggest that the combined expression of Notch3 and pTalpha sustains T cell leukemogenesis and may represent pathognomonic molecular features of human T-ALL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Cell Transformation, Neoplastic / genetics
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Child
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Flow Cytometry
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Gene Deletion
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Gene Expression Regulation, Neoplastic*
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Homeodomain Proteins / genetics
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Humans
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Immunophenotyping
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Leukemia, T-Cell / genetics
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Leukemia, T-Cell / immunology
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Leukemia, T-Cell / metabolism*
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Leukemia, T-Cell / pathology
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Leukemia-Lymphoma, Adult T-Cell / genetics
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Leukemia-Lymphoma, Adult T-Cell / immunology
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Leukemia-Lymphoma, Adult T-Cell / metabolism
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Leukemia-Lymphoma, Adult T-Cell / pathology
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Transgenic
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor, Notch1
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Receptor, Notch3
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Receptor, Notch4
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Receptors, Antigen, T-Cell / deficiency
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / metabolism*
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Cell Surface*
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Receptors, Notch
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Spleen / immunology
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Spleen / metabolism
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Thymus Gland / immunology
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Thymus Gland / metabolism
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Transcription Factor HES-1
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Transcription Factors*
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Hes1 protein, mouse
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Homeodomain Proteins
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Membrane Glycoproteins
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Membrane Proteins
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NOTCH1 protein, human
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NOTCH3 protein, human
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Notch1 protein, mouse
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Notch3 protein, mouse
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptor, Notch1
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Receptor, Notch3
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Receptor, Notch4
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Receptors, Antigen, T-Cell
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Cell Surface
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Receptors, Notch
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Transcription Factor HES-1
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Transcription Factors
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pre-T cell receptor alpha
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Notch4 protein, mouse
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HES1 protein, human