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Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma
Published on: March 30, 2018
Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival:
Silvia Marcé1, Olga Balagué, Luis Colomo
1Pathology Department, Hematopathology Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
Purpose:
To determine the methylthioadenosine phosphorylase (MTAP) gene alterations in mantle cell lymphoma (MCL) and to investigate whether the targeted inactivation of the alternative de novo AMP synthesis pathway may be a useful therapeutic strategy in tumors with inactivation of this enzyme.
Experimental Design:
MTAP gene deletion and protein expression were studied in 64 and 52 primary MCL, respectively, and the results were correlated with clinical behavior. Five MCL cell lines were analyzed for MTAP expression and for the in vitro sensitivity to L-alanosine, an inhibitor of adenylosuccinate synthetase, and hence de novo AMP synthesis.
Results:
No protein expression was detected in 8 of 52 (15%) tumors and one cell line (Granta 519). Six of these MTAP negative tumors and Granta 519 cell line had a codeletion of MTAP and p16 genes; one case showed a deletion of MTAP, but not p16, and one tumor had no deletions in neither of these genes. Patients with MTAP deletions had a significant shorter overall survival (mean, 16.1 months) than patients with wild-type MTAP (mean, 63.6 months; P < 0.0001). L-Alanosine induced cytotoxicity and activation of the intrinsic mitochondrial-dependent apoptotic pathway in MCL cells. 9-beta-D-Erythrofuranosyladenine, an analogue of 5'-methylthioadenosine, selectively rescued MTAP-positive cells from L-alanosine toxicity.
Conclusions:
MTAP gene deletion and lack of protein expression are associated with poor prognosis in MCL and might identify patients who might benefit from treatment with de novo AMP synthesis pathway-targeted therapies.
Insights
Methylthioadenosine phosphorylase (MTAP) gene deletion in mantle cell lymphoma (MCL) indicates poor prognosis. Targeting the de novo AMP synthesis pathway may benefit MTAP-deficient MCL patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma.
- Methylthioadenosine phosphorylase (MTAP) is a key enzyme in purine metabolism.
- Alterations in MTAP may impact lymphoma development and treatment response.
Purpose of the Study:
- To investigate methylthioadenosine phosphorylase (MTAP) gene alterations in MCL.
- To assess the prognostic significance of MTAP alterations in MCL.
- To evaluate the therapeutic potential of targeting the de novo AMP synthesis pathway in MTAP-deficient MCL.
Main Methods:
- Analysis of MTAP gene deletion and protein expression in 64 and 52 primary MCL samples, respectively.
- Correlation of MTAP status with clinical outcomes.
- In vitro sensitivity testing of MCL cell lines to L-alanosine, an inhibitor of de novo AMP synthesis.
Main Results:
- MTAP deletion and lack of protein expression were observed in 15% of MCL tumors.
- MTAP deletions were significantly associated with shorter overall survival in MCL patients (16.1 vs. 63.6 months).
- L-alanosine induced cytotoxicity in MCL cells, and 9-beta-D-erythrofuranosyladenine selectively rescued MTAP-positive cells.
Conclusions:
- MTAP gene deletion and absence of protein expression are linked to poor prognosis in MCL.
- MTAP-deficient MCL patients may benefit from therapies targeting the de novo AMP synthesis pathway.
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