Notch and T cell malignancy
Introduction
The evolutionarily conserved Notch signaling pathway is involved in critical developmental decisions in a wide variety of tissues and organisms [1], [2]. Of note, the mammalian Notch1 receptor was initially identified as a translocation partner at a recurrent breakpoint in a subset of human T cell lymphomas [3]. It is now clear that constitutive Notch signaling in hematopoietic progenitors disrupts both normal T and B cell development and leads exclusively to T cell malignancies. Since these discoveries, many studies have provided clues into the role of Notch in leukemogenesis. Links to many well-known genes and pathways have been explored and this information will be reviewed here. Mechanisms by which dysregulated Notch signaling promotes lymphoid malignancy include effects on cell fate, differentiation, proliferation, and survival. Recent studies providing insights into these mechanisms will also be reviewed.
Section snippets
The t(7;9) translocation
The Notch1 receptor was identified as a recurrent t(7;9) breakpoint in a small subset of human T cell acute lymphoblastic lymphomas [3]. Four patients were initially described with this translocation in T cell lymphomas, all of whom were male, between 3 and 17 years old, and presented with a mediastinal mass and hepatosplenomegaly. Phenotypically their lymphomas were CD4+/CD8+, and CD5+/CD7+/CD1a+, suggesting that these were immature T cells, arrested as double positive (DP) cortical thymocytes
Notch in T cell development
Unlike T cell oncogenes such as Hox11 and Tal1 that are not normally expressed in developing T cells, Notch directs multiple developmental events in this lineage. Therefore, the oncogenic functions of Notch in T cell malignancies are likely to result from dysregulation of its role in normal T cell development. Thus, we will briefly review the functions of Notch in normal T cell development before considering its role in neoplasia. Notch signaling is critical for normal T cell differentiation
Murine models
Direct proof that dysregulated Notch signaling caused the t(7;9) T lymphomas was provided by results from murine models in which constitutive Notch signals induced T cell tumors. In bone marrow transplant (BMT) reconstitution models in which retrovirally transduced hematopoietic stem cells were transferred to lethally irradiated recipients, constitutive expression of the entire intracellular domain of human Notch1 (ICN1) led exclusively to CD8+CD24+ (immature single positive, ISP) or CD4+CD8+
Oncogenic cooperation
In murine models, Notch-induced T cell malignancies are clonal, suggesting that other events cooperate with dysregulated Notch signals. As discussed previously, pre-TCR signaling is necessary for Notch oncogenesis. Active pre-TCR signaling likely provides a permissive environment for oncogenesis by providing enhanced proliferation and differentiation that cooperate with Notch signaling. Therefore, pre-TCR signaling may define a subset of T cell precursors capable of Notch-mediated
Other potential cooperating events
Additional potential cooperative signals may be identified through retroviral insertional mutagenesis screens. A brief review of such data collected at the NCI’s Retroviral Tagged Cancer Gene Database RTCGD (http://RTCGD.ncifcrf.gov) reveals that the Notch pathway is frequently targeted in lymphoid leukemias (33 independent tumors) (see Table 1) [85]. Many members of the Notch pathway are present including the Notch1 and Notch2 receptors, the Notch receptor modifier Lunatic Fringe, CSL, the
Treatment strategies
Although it appears that <1% of all human T cell malignancies contain the t(7;9) translocation, some data suggests that dysregulation of Notch signaling may be a more common occurrence in human leukemia/lymphomas. For example, high levels of Notch1 protein expression were found in twelve primary human T cell anaplastic large cell lymphoma (ALCL) samples as compared to B cell lymphomas, and high levels of cleaved (activated) Notch1 were seen in two human ALCL-derived cell lines, compared to
How frequently does Notch dysregulation have a role in T cell transformation?
Notch1 translocations are present in <1% of all T cell malignancies. However, recent evidence suggests that Notch3 is co-expressed with pre-TCR signaling in a majority of human T cell leukemias [9]. Whether Notch is required for the malignant phenotype of these tumors or serves as a differentiation marker is not yet known. One method to test the former is to treat these tumor cells with gamma secretase inhibitors to assay their dependence on persistent Notch signals. However, if
Summary
Constitutive Notch signaling leads to T cell leukemias/lymphomas in mice and humans. Despite more than a decade of work and a rapidly expanding knowledge of Notch pathway functions and interactions, the basic mechanism for Notch-mediated lymphomagenesis still eludes us. The existence of differing Notch receptor truncations and cooperation with multiple oncogenes suggests that this mechanism will likely be complex and may not only depend on constitutive Notch signaling, but also on additional
Acknowledgements
We would like to thank Jon Aster, and the members of the Pear lab for contributing suggestions and revising this manuscript. Patrick Zweidler-McKay is supported by NCI grant 1K08CA101934-01A1. Warren S. Pear is supported by grants from the National Institutes of Health and the Leukemia and Lymphoma Society SCOR Program.
References (92)
- et al.
TAN-1, the human homolog of the Drosophila notch gene is broken by chromosomal translocations in T lymphoblastic neoplasms
Cell
(1991) - et al.
Clinical and biological characterization of T cell neoplasias with rearrangements of chromosome 7 band q34
Blood
(1988) - et al.
Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma
Blood
(2002) - et al.
Gene expression profiling in T-cell acute lymphoblastic leukemia
Semin. Hematol.
(2003) - et al.
Notch and the immune system
Immunity
(2003) - et al.
Notch1 expression in early lymphopoiesis influences B versus T lineage determination
Immunity
(1999) - et al.
Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development
Immunity
(2003) - et al.
Modulated expression of notch1 during thymocyte development
Blood
(1996) - et al.
Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta lineage thymocytes
Immunity
(2002) - et al.
Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes
Immunity
(2000)
Notch1 regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength
Immunity
An activated form of Notch influences the choice between CD4 and CD8 T cell lineages
Cell
Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-induced T cell leukemogenesis
Cancer Cell
Correlating notch signaling with thymocyte maturation
Immunity
Structural requirements for assembly of the CSL.intracellular Notch1.Mastermind-like 1 transcriptional activation complex
J. Biol. Chem.
A novel Notch ligand Dll4 induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer
Blood
Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease
Blood
Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1
Immunity
Requirement for cyclin D3 in lymphocyte development and T cell leukemias
Cancer Cell
Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor
Cell
Evidence that an IRES within the Notch2 coding region can direct expression of a nuclear form of the protein
Mol. Cell
Loss of CBP causes T cell lymphomagenesis in synergy with p27Kip1 insufficiency
Cancer Cell
Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors
J. Biol. Chem.
Chronic treatment with the {gamma}-secretase inhibitor LY-411,575 inhibits {beta}-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation
J. Biol. Chem.
Secretases as targets for the treatment of Alzheimer’s disease: the prospects
Lancet Neurol.
Notch signaling
Science
LIN-12/Notch signaling: lessons from worms and flies
Genes Dev.
Cytogenetics and molecular genetics of childhood leukemia
Hematol. Oncol.
Differential regulation of Notch signal transduction in leukaemia and lymphoma cells in culture
J. Cell Biochem.
A notch-independent activity of suppressor of hairless is required for normal mechanoreceptor physiology
Cell
Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis
Proc. Natl. Acad. Sci. U.S.A.
Notch regulation of lymphocyte development and function
Nat. Immunol.
Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles
J. Exp. Med.
Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus
J. Exp. Med.
Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision
Int. Immunol.
Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation
Genesis
Notch signaling is essential for vascular morphogenesis in mice
Genes Dev.
Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway
Genes Dev.
Notch ligation by Delta1 inhibits peripheral immune responses to transplantation antigens by a CD8+ cell-dependent mechanism
J. Clin. Invest.
Notch signaling augments T cell responsiveness by enhancing CD25 expression
J. Immunol.
Serrate1-induced notch signalling regulates the decision between immunity and tolerance made by peripheral CD4(+) T cells
Int. Immunol.
TCR-mediated notch signaling regulates proliferation and IFN-gamma production in peripheral T cells
J. Immunol.
Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by Notch1
Mol. Cell. Biol.
Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells
J. Exp. Med.
Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling
Mol. Cell. Biol.
Cited by (43)
HES1 in immunity and cancer
2016, Cytokine and Growth Factor ReviewsCitation Excerpt :Signalling mediated by the NOTCH pathway plays an important role in cellular functions such as proliferation, differentiation, survival and apoptosis [14]. NOTCH plays complex opposing roles depending on the cellular context: in mammary adenocarcinoma and T-cell acute lymphoblastic leukaemia (ALL) it functions as an oncogene whereas, in contrast, it acts as a tumour suppressor in B cell and neuroendocrine malignancies ([15–18]. Upon binding of the ligand (Jagged 1, 2, and Delta-like (Dll) 1, 3, 4) to the NOTCH receptor, there is a cascade of events which results in the exposure of cleaving sites for ADAM 10 and Y secretase resulting in the release of the intracellular domain of the NOTCH receptor (NICD).
Oncogenic activation of the Notch1 gene by deletion of its promoter in Ikaros-deficient T-ALL
2010, BloodCitation Excerpt :These have provided valuable information about the potential of activated proteins to induce transformation, but they also come with caveats, as overexpression studies do not always resemble the physiologic disease. For example, overexpression of intracellular Notch1-3 are equally capable of inducing leukemia in the retroviral bone marrow transfer model,16 yet Notch2 does not appear to be affected in human T-ALL. Thus, the individual roles played by the specific Notch receptors in T-ALL progression remain poorly understood.
Ikaros directly represses the notch target gene Hes1 in a leukemia T cell line: Implications for CD4 regulation
2008, Journal of Biological ChemistryLef-1: NOTCHed up in T-cell lymphomas
2007, Bloodβ-catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation
2007, BloodCitation Excerpt :Of interest, both β-catenin stabilization and constitutive Notch activation induce a developmental block at the DP stage.53 It has recently been proposed that this developmental block may be at the basis of Notch's ability to transform thymocytes.37 By analogy, it is possible that transformation induced by β-catenin is assisted by the developmental block at the DP stage.
NOTCH Signaling in Osteosarcoma
2023, Current Issues in Molecular Biology