The impact of SAMHD1 expression and mutation status in mantle cell lymphoma: An analysis of the MCL Younger and Elderly trial.

Tobias Roider, Xi Wang, Katrin Hüttl, Carsten Müller-Tidow, Wolfram Klapper, Andreas Rosenwald, James Peter Stewart, David Gonzalez de Castro, Peter Dreger, Olivier Hermine, Hanneke C Kluin-Nelemans, Niels Grabe, Martin Dreyling, Christiane Pott, German Ott, Eva Hoster, Sascha Dietrich

Journal: International journal of cancer 2021;148(1):150-160

PMID: 32638373

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Abstract

The sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) has been demonstrated to predict the response to high-dose cytarabine consolidation treatment in acute myeloid leukemia patients. Here, we evaluated SAMHD1 as potential biomarker for the response to high-dose cytarabine in mantle cell lymphoma (MCL) patients. We quantified SAMHD1 protein expression and determined the mutation status in patients of the MCL Younger and Elderly trials (n = 189), who had received high-dose cytarabine- or fludarabine-based polychemotherapy. Additionally, we quantified SAMHD1 expression in B cell lymphoma cell lines and exposed them to cytarabine, fludarabine, and clinically relevant combinations. Across both trials investigated, SAMHD1 mutations had a frequency of 7.1% (n = 13) and did not significantly affect the failure-free survival (FFS, P = .47). In patients treated with high-dose cytarabine- or fludarabine-containing regimes, SAMHD1 expression was not significantly associated with FFS or complete remission rate. SAMHD1 expression in B cell lymphoma cell lines, however, inversely correlated with their in vitro response to cytarabine as single agent (R = .65, P = .0065). This correlation could be reversed by combining cytarabine with other chemotherapeutics, such as oxaliplatin and vincristine, similar to the treatment regime of the MCL Younger trial. We conclude that this might explain why we did not observe a significant association between SAMHD1 protein expression and the outcome of MCL patients upon cytarabine-based treatment.

Address: Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.; Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Department of Clinical Pathology, Robert-Bosch-Hospital, Stuttgart, Germany.; Department of Pathology, University of Schleswig-Holstein, Campus Kiel, Kiel, Germany.; Institute of Pathology, University of Würzburg, Würzburg, Germany.; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.; Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.; Hôpital Necker-Enfants Malades, Paris, France.; Department of Hematology, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands.; Hamamatsu Tissue Imaging and Analysis Center (TIGA), Bioquant, University of Heidelberg, Heidelberg, Germany.; Department of Medicine III, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.; Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Germany.; Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität Munich, Munich, Germany.

DOI: 10.1002/ijc.33202

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MeSH Terms: Adult, Age Factors, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Cell Line, Tumor, Cyclophosphamide, Cytarabine, DNA Mutational Analysis, Disease-Free Survival, Dose-Response Relationship, Drug, Doxorubicin, Drug Resistance, Neoplasm, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Lymphoma, B-Cell, Lymphoma, Mantle-Cell, Male, Middle Aged, Mutation, Oxaliplatin, Prednisone, Primary Cell Culture, Rituximab, SAM Domain and HD Domain-Containing Protein 1, Tissue Array Analysis, Vidarabine, Vincristine