Targeting the NF-κB signaling pathway in Notch1-induced T-cell leukemia (original) (raw)

Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice

The EMBO Journal, 2000

The multiplicity of Notch receptors raises the question of the contribution of speci®c isoforms to T-cell development. Notch3 is expressed in CD4 ± 8 ± thymocytes and is down-regulated across the CD4 ± 8 ± to CD4 + 8 + transition, controlled by pre-T-cell receptor signaling. To determine the effects of Notch3 on thymocyte development, transgenic mice were generated, expressing lck promoter-driven intracellular Notch3. Thymuses of young transgenics showed an increased number of thymocytes, particularly late CD4 ± 8 ± cells, a failure to down-regulate CD25 in post-CD4 ± 8 ± subsets and sustained activity of NF-kB. Subsequently, aggressive multicentric T-cell lymphomas developed with high penetrance. Tumors sustained characteristics of immature thymocytes, including expression of CD25, pTa and activated NF-kB via IKKa-dependent degradation of IkBa and enhancement of NF-kBdependent anti-apoptotic and proliferative pathways. Together, these data identify activated Notch3 as a link between signals leading to NF-kB activation and T-cell tumorigenesis. The phenotypes of pre-malignant thymocytes and of lymphomas indicate a novel and particular role for Notch3 in coordinating growth and differentiation of thymocytes, across the pre-T/T cell transition, consistent with the normal expression pattern of Notch3.

Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia

The EMBO Journal, 2006

Notch signaling plays a critical role in T-cell differentiation and leukemogenesis. We previously demonstrated that, while pre-TCR is required for thymocytes proliferation and leukemogenesis, it is dispensable for thymocyte differentiation in Notch3-transgenic mice. Notch3-transgenic premalignant thymocytes and T lymphoma cells overexpress pTa/pre-TCR and display constitutive activation of NF-jB, providing survival signals for immature thymocytes. We provide genetic and biochemical evidence that Notch3 triggers multiple NF-jB activation pathways. A pre-TCR-dependent pathway preferentially activates NF-jB via IKKb/IKKa/NIK complex, resulting in p50/p65 heterodimer nuclear entry and recruitment onto promoters of Cyclin D1, Bcl2-A1 and IL7-receptor-a genes. In contrast, upon pTa deletion, Notch3 binds IKKa and maintains NF-jB activation through an alternative pathway, depending on an NIK-independent IKKa homodimer activity. The consequent NF-jB2/p100 processing allows nuclear translocation of p52/RelB heterodimers, which only trigger transcription from Bcl2-A1 and IL7-receptor-a genes. Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-jB activity, leading to differential NF-jB subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/ leukemogenesis.

The Notch/Hes1 Pathway Sustains NF-κB Activation through CYLD Repression in T Cell Leukemia

Cancer Cell, 2010

It was previously shown that the NF-kB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-kB activation using both human TALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in TALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary TALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of TALL as specific suppression of IKK expression and function affected both the survival of human TALL cells and the maintenance of the disease in vivo.

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

Frontiers in Immunology

The Notch signaling pathway plays multiple roles in driving T-cell fate decisions, proliferation, and aberrant growth. NF-κB is a cell-context key player interconnected with Notch signaling either in physiological or in pathological conditions. This review focuses on how the multilayered crosstalk between different Notches and NF-κB subunits may converge on Foxp3 gene regulation and orchestrate CD4 + regulatory T (Treg) cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor growth. A future challenge is represented by further dissection of both Notch and NF-κB pathways and consequences of their intersection in tumor-associated Treg biology. This may shed light on the molecular mechanisms regulating Treg cell expansion and migration to peripheral lymphoid organs thought to facilitate tumor development and still to be explored. In so doing, new opportunities for combined and/or more selective therapeutic approaches to improve anticancer immunity may be found.

Notch-1 Regulates NF-κB Activity in Hemopoietic Progenitor Cells

The Journal of Immunology, 2001

We investigated the interaction between two elements critical for differentiation of hemopoietic cells, the Notch-1 receptor and the transcription factor NF-κB. These factors were studied in hemopoietic progenitor cells (HPC) using Notch-1 antisense transgenic (Notch-AS-Tg) mice. DNA binding of NF-κB as well as its ability to activate transcription was strongly decreased in HPC from Notch-AS-Tg mice. NF-κB-driven transcriptional activity was completely restored after transduction of the cells with retroviral constructs containing activated Notch-1 gene. HPC from Notch-AS-Tg mice have decreased levels of several members of the NF-κB family, p65, p50, RelB, and c-Rel and this is due to down-regulation of the gene expression. To investigate functional consequences of decreased NF-κB activity in transgenic mice, we studied LPS-induced proliferation of B cells and GM-CSF-dependent differentiation of dendritic cells from HPC. These two processes are known to be closely dependent on NF-κB....

Cells Activity in Hemopoietic Progenitor Notch1 Regulates NF{kappa}B

We investigated the interaction between two elements critical for differentiation of hemopoietic cells, the Notch-1 receptor and the transcription factor NF-B. These factors were studied in hemopoietic progenitor cells (HPC) using Notch-1 antisense transgenic (Notch-AS-Tg) mice. DNA binding of NF-B as well as its ability to activate transcription was strongly decreased in HPC from Notch-AS-Tg mice. NF-B-driven transcriptional activity was completely restored after transduction of the cells with retroviral constructs containing activated Notch-1 gene. HPC from Notch-AS-Tg mice have decreased levels of several members of the NF-B family, p65, p50, RelB, and c-Rel and this is due to down-regulation of the gene expression. To investigate functional consequences of decreased NF-B activity in transgenic mice, we studied LPS-induced proliferation of B cells and GM-CSFdependent differentiation of dendritic cells from HPC. These two processes are known to be closely dependent on NF-B. B cells from Notch-AS-Tg mice had almost 3-fold lower response to LPS than B cells isolated from control mice. Differentiation of dendritic cells was significantly affected in Notch-AS-Tg mice. However, it was restored by transduction of activated Notch-1 into HPC. Taken together, these data indicate that in HPC NF-B activity is regulated by Notch-1 via transcriptional control of NF-B.