Article

Growth Suppression of Pre-T Acute Lymphoblastic Leukemia Cells by Inhibition of Notch Signaling

Departments of Pathology, Brigham and Women's Hospital, Harvard Medical School. Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Molecular and Cellular Biology (Impact Factor: 5.04). 02/2003; 23(2):655-64. DOI: 10.1128/MCB.23.2.655-664.2003
Source: PubMed

ABSTRACT Constitutive NOTCH signaling in lymphoid progenitors promotes the development of immature T-cell lymphoblastic neoplasms (T-ALLs). Although it is clear that Notch signaling can initiate leukemogenesis, it has not previously been established whether continued NOTCH signaling is required to maintain T-ALL growth. We demonstrate here that the blockade of Notch signaling at two independent steps suppresses the growth and survival of NOTCH1-transformed T-ALL cells. First, inhibitors of presenilin specifically induce growth suppression and apoptosis of a murine T-ALL cell line that requires presenilin-dependent proteolysis of the Notch receptor in order for its intracellular domain to translocate to the nucleus. Second, a 62-amino-acid peptide derived from a NOTCH coactivator, Mastermind-like-1 (MAML1), forms a transcriptionally inert nuclear complex with NOTCH1 and CSL and specifically inhibits the growth of both murine and human NOTCH1-transformed T-ALLs. These studies show that continued growth and survival of NOTCH1-transformed lymphoid cell lines require nuclear access and transcriptional coactivator recruitment by NOTCH1 and identify at least two steps in the Notch signaling pathway as potential targets for chemotherapeutic intervention.

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    • "To test activation of the Notch pathway, we used a construct that encodes the constitutively active, cleaved form of Notch1 (intracellular notch 1 [ICN1]), as well as GFP (Pui et al., 1999). To test inhibition of the Notch pathway, we used a dominant–negative form of the Notch cofactor Mastermind-like1 (dnMAML), which blocks canonical Notch signaling from all four of the Notch receptors (Weng et al., 2003). These constructs, or the GFPonly vector (MigR1), were used to transduce AML cells, as previously described (Zweidler-McKay et al., 2005). "
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    ABSTRACT: Although aberrant Notch activation contributes to leukemogenesis in T cells, its role in acute myelogenous leukemia (AML) remains unclear. Here, we report that human AML samples have robust expression of Notch receptors; however, Notch receptor activation and expression of downstream Notch targets are remarkably low, suggesting that Notch is present but not constitutively activated in human AML. The functional role of these Notch receptors in AML is not known. Induced activation through any of the Notch receptors (Notch1-4), or through the Notch target Hairy/Enhancer of Split 1 (HES1), consistently leads to AML growth arrest and caspase-dependent apoptosis, which are associated with B cell lymphoma 2 (BCL2) loss and enhanced p53/p21 expression. These effects were dependent on the HES1 repressor domain and were rescued through reexpression of BCL2. Importantly, activated Notch1, Notch2, and HES1 all led to inhibited AML growth in vivo, and Notch inhibition via dnMAML enhanced proliferation in vivo, thus revealing the physiological inhibition of AML growth in vivo in response to Notch signaling. As a novel therapeutic approach, we used a Notch agonist peptide that led to significant apoptosis in AML patient samples. In conclusion, we report consistent Notch-mediated growth arrest and apoptosis in human AML, and propose the development of Notch agonists as a potential therapeutic approach in AML.
    Journal of Experimental Medicine 01/2013; 210(2). DOI:10.1084/jem.20121527 · 13.91 Impact Factor
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    • "Retroviral vectors all used the MSCV-IRES-GFP (Mig) backbone. Mig ICN1, Mig E, and MSCV-DN-MAML1-GFP have been described previously (Aster et al., 1997; Weng et al., 2003). Mig IGF1R was generated by subcloning a 4.2-kb NotI-BamHI fragment containing the human IGF1R cDNA from pBABE-bleo IGF1R (Addgene) into the Mig vector. "
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    ABSTRACT: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of Notch1 and PI3K-Akt pathways. Although mutations that activate PI3K-Akt signaling have previously been identified, the relative contribution of growth factor-dependent activation is unclear. We show here that pharmacologic inhibition or genetic deletion of insulin-like growth factor 1 receptor (IGF1R) blocks the growth and viability of T-ALL cells, whereas moderate diminution of IGF1R signaling compromises leukemia-initiating cell (LIC) activity as defined by transplantability in syngeneic/congenic secondary recipients. Furthermore, IGF1R is a Notch1 target, and Notch1 signaling is required to maintain IGF1R expression at high levels in T-ALL cells. These findings suggest effects of Notch on LIC activity may be mediated in part by enhancing the responsiveness of T-ALL cells to ambient growth factors, and provide strong rationale for use of IGF1R inhibitors to improve initial response to therapy and to achieve long-term cure of patients with T-ALL.
    Journal of Experimental Medicine 08/2011; 208(9):1809-22. DOI:10.1084/jem.20110121 · 13.91 Impact Factor
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    • "Cell cycle progression is regulated at several checkpoints of cellular process. Notch signaling has been shown to be a potent regulator of cell cycle progression in T-ALL cells [86] [89] [112]. Sicinski and colleagues [113] have studied the function of cyclin D3 in T-cell development and T-cell leukemogenesis, and they found that cyclin D3 −/− ) mice show impaired expansion of immature T lymphocytes, characterized by a marked deficit of CD4 + CD8 + T cells. "
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    ABSTRACT: The Notch signaling pathway is an evolutionarily conserved cell signaling system present in most multicellular organisms, as it controls cell fate specification by regulating cell proliferation, differentiation, apoptosis, and survival. Regulation of the Notch signaling pathway can be achieved at multiple levels. Notch proteins are involved in lineage fate decisions in a variety of tissues in various species. Notch is essential for T lineage cell differentiation including T versus B and αβ versus γδ lineage specification. In this paper, we discuss Notch signaling in normal T-cell maturation and differentiation as well as in T-cell acute lymphoblastic lymphoma/leukemia.
    01/2011; 2011:921706. DOI:10.5402/2011/921706
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