Background: Malignant cells from different cancers express different profiles of chemokine receptors (CKR). Their presence may influence site-specific spread of tumor cells, by enabling them to respond to chemokine gradient, and may increase cell sensibility to chemokine mediated proliferative and anti-apoptotic stimuli. Notch ability to positively regulate CKR has been reported: stimulation of Pax5-/- pre-B cells with the Notch ligand Delta-1 results in induction of transcripts for CCR4, CCR8 and CXCR 6; the Delta-1-dependent regulation of Langerhans cell development includes induction of CCR6 expression resulting in the activation of chemotactic response to MIP-1a; Notch controls CCR7 signaling a regulator of CNS infiltration in T-acute lymphoblastic leukemia (T-ALL). Methods: This work aims to explore the correlation between the activation of the Notch oncogenic pathway in T-ALL and multiple myeloma (MM) cells and the aberrant expression CKR. Human T-ALL cell lines were treated with the Notch activation inhibitor, DAPT, or with a potent inhibitor of the Notch target, C-MYC, and evaluated the expression and functions of CCR9, CCR5, and CXCR4. Results: Treatment of human T-ALL and MM cell lines with pharmacologic inhibitors of Notch receptor activation produced a significant reduction of CCR9, CCR5 and CXCR4 expression, at both mRNA and protein levels. Results were confirmed by chemotaxis and survival assays. We identified the product of C-MYC gene as a possible mediator of Notch effect in regulating CKR networks in T-ALL and MM. Conclusions: These results suggest that Notch receptors play a previously unknown role in cancer progression and metastasis, by maintaining the expression levels of CKR. In conclusion, the identification of the potential axis Notch/CKR could have a prognostic value and provide the rationale for a tailored approach, since both Notch and CKR are targeted by emerging drugs.
Chemokine receptors as novel targets of the oncogene Notch1 in acute lymphoblastic leukemia / L. Mirandola, M. Chiriva-Internati, E. Cobos, Y. Yu, J.A. Figueroa, S. Garavelli, M. Colombo, E. Lazzari, N. Platonova, K. Zepeda, C.A. Jumper, M. Jenkins, R. Alalawi, V. Konala, A. Aulakh, S. Radhi, R. Chiaramonte. - In: JOURNAL OF CLINICAL ONCOLOGY. - ISSN 1527-7755. - 31:15(2013 Jun 02), p. e22052. ((Intervento presentato al convegno ASCO Annual Meeting tenutosi a Chicago, IL nel 2013.
|Titolo:||Chemokine receptors as novel targets of the oncogene Notch1 in acute lymphoblastic leukemia|
MIRANDOLA, LEONARDO (Primo)
CHIARAMONTE, RAFFAELLA (Ultimo)
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore MED/05 - Patologia Clinica
|Data di pubblicazione:||2-giu-2013|
|Appare nelle tipologie:||01 - Articolo su periodico|