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: 7.59). 10/2011; 226(5):713-22. DOI: 10.1002/path.3015
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The gastrointestinal (GI) tract is the most common site of extranodal B-cell lymphomas. However, it is unclear how neoplastic lymphoid cells preferentially home there. We hypothesize that expression of the gastrointestinal-homing chemokine receptor CCR9 may account for the dissemination of B-cell lymphomas to the gastrointestinal tract. To test our hypothesis, we compared the expression of CCR9 using immunohistochemistry on GI versus nodal diffuse large B-cell lymphoma and follicular lymphoma. We found that 27/41 (66%), 12/41 (29%), and 2/41 (5%) of GI lymphoma cases demonstrated 3+, 2+, and 1+ CCR9 staining, respectively. In contrast, 2/39 (5%), 5/39 (13%), 8/39 (20.5%), and 24/39 (61.5%) nodal-restricted lymphoma cases demonstrated 3+, 2+, 1+ and 0+ CCR9 staining (P<0.0001). This was observed for both diffuse large B-cell lymphoma (P<0.001) and follicular lymphoma (P<0.001). We also compared the expression of CCR9 on nodal B-cell lymphomas with involvement of the gastrointestinal tract to those restricted to the lymph node. We found that 10/16 (62%), 3/16 (19%), and 3/16 (19%) nodal lymphomas with gastrointestinal involvement showed 3+, 2+ and 1+ CCR9 staining, respectively. In contrast, 2/39 (5%), 5/39 (13%), 8/39 (20.5%), and 24/39 (61.5%) nodal lymphomas without gastrointestinal involvement demonstrated 3+, 2+, 1+ and 0+ CCR9 staining, respectively (P<0.001). Our finding that CCR9 expression is elevated in the nodal lymphomas of patients with gastrointestinal involvement suggests the potential clinical utility of chemokine receptor status, as assessed by immunohistochemistry, to potentially predict gastrointestinal dissemination and progression to higher stage in patients who initially present with limited nodal-restricted disease.
    Human pathology 01/2014; · 3.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 01/2014; 2014:924030.
  • [Show abstract] [Hide abstract]
    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; 2014:126954. · 2.14 Impact Factor

Full-text (2 Sources)

Available from
Jun 4, 2014