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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    • "1 (IGF1)], chemokines, Notch ligands (DLL4) and adhesion molecules (e.g. ICAM1) (Winter et al, 2001; Buonamici et al, 2009; Medyouf et al, 2011; Silva et al, 2011; Mirandola et al, 2012; Uzan et al, 2014; Minuzzo et al, 2015). Furthermore, our group has found that expression of the NF-jB transcription factor RELB in non-haematopoietic stromal cells contributes to the development of T-ALL in a mouse model (dos Santos et al, 2008). "
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    ABSTRACT: Lymphotoxin-mediated activation of the lymphotoxin-β receptor (LTβR; LTBR) has been implicated in cancer, but its role in T-cell acute lymphoblastic leukaemia (T-ALL) has remained elusive. Here we show that the genes encoding lymphotoxin (LT)-α and LTβ (LTA, LTB) are expressed in T-ALL patient samples, mostly of the TAL/LMO molecular subtype, and in the TEL-JAK2 transgenic mouse model of cortical/mature T-ALL (Lta, Ltb). In these mice, expression of Lta and Ltb is elevated in early stage T-ALL. Surface LTα1 β2 protein is expressed in primary mouse T-ALL cells, but only in the absence of microenvironmental LTβR interaction. Indeed, surface LT expression is suppressed in leukaemic cells contacting Ltbr-expressing but not Ltbr-deficient stromal cells, both in vitro and in vivo, thus indicating that dynamic surface LT expression in leukaemic cells depends on interaction with its receptor. Supporting the notion that LT signalling plays a role in T-ALL, inactivation of Ltbr results in a significant delay in TEL-JAK2-induced leukaemia onset. Moreover, young asymptomatic TEL-JAK2;Ltbr-/- mice present markedly less leukaemic thymocytes than age-matched TEL-JAK2;Ltbr+/+ mice and interference with LTβR function at this early stage delayed T-ALL development. We conclude that LT expression by T-ALL cells activates LTβR signalling in thymic stromal cells, thus promoting leukaemogenesis.
    Full-text · Article · Oct 2015 · British Journal of Haematology
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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.
    Full-text · Article · Apr 2014 · Advances in Hematology
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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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