NOTCH1 regulates chemotaxis and proliferation by controlling the CC-chemokine receptors 5 and 9 in T cell acute lymphoblastic leukaemia

Department of Medicine, Surgery and Dentistry, Università degli Studi di Milano, Milan, Italy.
The Journal of Pathology (Impact Factor: 7.43). 04/2012; 226(5):713-22. DOI: 10.1002/path.3015
Source: PubMed


Tumour cells often express deregulated profiles of chemokine receptors that regulate cancer cell migration and proliferation. Notch1 pathway activation is seen in T cell acute lymphoblastic leukaemia (T-ALL) due to the high frequency of Notch1 mutations affecting approximately 60% of patients, causing ligand-independent signalling and/or prolonging Notch1 half-life. We have investigated the possible regulative role of Notch1 on the expression and function of chemokine receptors CCR5, CCR9 and CXCR4 that play a role in determining blast malignant properties and localization of extramedullary infiltrations in leukaemia. We inhibited the pathway through γ-Secretase inhibitor and Notch1 RNA interference and analysed the effect on the expression and function of chemokine receptors. Our results indicate that γ-Secretase inhibitor negatively regulates the transcription level of the CC chemokine receptors 5 and 9 in T-ALL cell lines and patients' primary leukaemia cells, leaving CXCR4 expression unaltered. The Notch pathway also controls CCR5- and CCR9-mediated biological effects, ie chemotaxis and proliferation. Furthermore, engaging CCR9 through CCL25 administration rescues proliferation inhibition associated with abrogation of Notch activity. Finally, through RNA interference we demonstrated that the oncogenic isoform in T-ALL, Notch1, plays a role in controlling CCR5 and CCR9 expression and functions. These findings suggest that Notch1, acting in concert with chemokine receptors pathways, may provide leukaemia cells with proliferative advantage and specific chemotactic abilities, therefore influencing tumour cell progression and localization.

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Available from: Leonardo Mirandola,
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    • "Aster and colleagues [14] showed that T-cell ALL is a disease primarily caused by aberrant activation of the NOTCH1 signaling pathway. In this context, expression and function of important chemokine receptors, such as CCR5 and CCR9, are partially controlled by the oncogenic NOTCH1 isoform in T-cell ALL, regulating blast malignant properties and localization of extramedullary infiltrations [15]. Additionally, CCR5 has been related to play a key role in metastasis of aggressive NK-cells leukemia to the liver of patients, contributing to hepatosplenomegaly and hepatic failure [16] [17]. "
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    ABSTRACT: Acute lymphoblastic leukemia (ALL) is a malignant disorder that originates from one single hematopoietic precursor committed to B- or T-cell lineage. Ordinarily, these cells express CCR5 chemokine receptor, which directs the immune response to a cellular pattern and is involved in cancer pathobiology. The genetic rs333 polymorphism of CCR5 (Δ32), results in a diminished receptor expression, thus leading to impaired cell trafficking. The objective of the present study was to investigate the effect of CCR5 chemokine receptor rs333 polymorphism in the pathogenesis of ALL. The genotype distribution was studied in 79 patients and compared with 80 control subjects, in a childhood population of Southern Brazil. Genotyping was performed using DNA samples amplified by polymerase chain reaction with sequence-specific primers (PCR-SSP). The homozygous (Δ32/Δ32) deletion was not observed in any subject involved in the study. Heterozygous genotype was not associated with ALL risk (OR 0.7%; 95% CI 0.21-2.32; P > 0.05), nor recurrence status of ALL (OR 0.86; 95% CI 0.13-5.48; P > 0.05). This work demonstrated, for the first time, no significant differences in the frequency of the CCR5/Δ32 genotype between ALL and control groups, indicating no effect of this genetic variant on the ALL susceptibility and recurrence risk.
    Advances in Hematology 04/2014; 2014(7):924030. DOI:10.1155/2014/924030
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    • "Notch pathway is a well-known factor in the development of lymphoid lineage [56–58]. Mirandola et al. [59] investigated the possible regulative role of Notch1 in the expression and function of chemokine receptors CCR5, CCR9, and CXCR4 that play a role in determining blast malignant properties and localization of extramedullary infiltrations in leukemia. In this context, these authors suggested that Notch1 pathway abnormalities trigger an increase of CCR5 and CCR9 expression on leukemic blasts. "
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    ABSTRACT: Solid tumors are embedded in a stromal microenvironment consisting of immune cells, such as macrophages and lymphocytes, as well as nonimmune cells, such as endothelial cells and fibroblasts. Chemokines are a type of small secreted chemotactic cytokine and together with their receptors play key roles in the immune defense. Critically, they regulate cancer cellular migration and also contribute to their proliferation and survival. The CCR5 chemokine receptor is involved in leucocytes chemotaxis to sites of inflammation and plays an important role in the macrophages, T cells, and monocytes recruitment. Additionally, CCR5 may have an indirect effect on cancer progression by controlling the antitumor immune response, since it has been demonstrated that its expression could promote tumor growth and contribute to tumor metastasis, in different types of malignant tumors. Furthermore, it was demonstrated that a CCR5 antagonist may inhibit tumor growth, consisting of a possible therapeutic target. In this context, the present review focuses on the establishment of CCR5 within the interface of host immunity, tumor microenvironment, and its potential as a targeting to immunotherapy.
    Disease markers 01/2014; 2014(7):126954. DOI:10.1155/2014/126954 · 1.56 Impact Factor
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    ABSTRACT: NOTCH1 receptor signaling plays a central role in T-cell lineage specification and in supporting the growth and proliferation of immature T-cell progenitors in the thymus during lymphoid development. In T-cell acute lymphoblastic leukemia (T-ALL), a tumor resulting from the malignant transformation of T-cell progenitors, aberrant and constitutively active NOTCH1 signaling triggered by activating mutations in the NOTCH1 gene contributes to oncogenic transformation and is a hallmark of this disease. Most notably, small molecule γ-secretase inhibitors (GSIs) can effectively block NOTCH1 signaling in T-ALL, and could be exploited as a targeted therapy in this disease. In addition, a number of emerging anti-NOTCH therapeutic strategies including anti-NOTCH1 inhibitory antibodies, small peptide inhibitors of NOTCH signaling and combination therapies with GSIs and glucocorticoids, have recently been proposed. Finally, the identification of NOTCH1 mutations in solid tumors and chronic lymphocytic leukemias has increased even further the clinical relevance of NOTCH signaling as a therapeutic target in human cancer. Here we review our current understanding of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 in T-ALL and the therapeutic and prognostic implications of NOTCH1 mutations in T-ALL.
    Current topics in microbiology and immunology 06/2012; 360:163-82. DOI:10.1007/82_2012_232 · 4.10 Impact Factor
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