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Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2016 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 24, p. 6217-6227Article in journal (Refereed) Published
Abstract [en]

Purpose: To identify resistance mechanisms for the chemotherapeutic drug fludarabine in chronic lymphocytic leukemia (CLL), as innate and acquired resistance to fludarabine-based chemotherapy represents a major challenge for long-term disease control. Experimental Design: We used piggyBac transposon-mediated mutagenesis, combined with next-generation sequencing, to identify genes that confer resistance to fludarabine in a human CLL cell line. Results: In total, this screen identified 782 genes with transposon integrations in fludarabine-resistant pools of cells. One of the identified genes is a known resistance mediator DCK (deoxycytidine kinase), which encodes an enzyme that is essential for the phosphorylation of the prodrug to the active metabolite. BMP2K, a gene not previously linked to CLL, was also identified as a modulator of response to fludarabine. In addition, 10 of 782 transposon-targeted genes had previously been implicated in treatment resistance based on somatic mutations seen in patients refractory to fludarabine-based therapy. Functional characterization of these genes supported a significant role for ARID5B and BRAF in fludarabine sensitivity. Finally, pathway analysis of transposon-targeted genes and RNA-seq profiling of fludarabine-resistant cells suggested deregulated MAPK signaling as involved in mediating drug resistance in CLL. Conclusions: To our knowledge, this is the first forward genetic screen for chemotherapy resistance in CLL. The screen pinpointed novel genes and pathways involved in fludarabine resistance along with previously known resistance mechanisms. Transposon screens can therefore aid interpretation of cancer genome sequencing data in the identification of genes modifying sensitivity to chemotherapy.

Place, publisher, year, edition, pages
2016. Vol. 22, no 24, p. 6217-6227
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Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-315914DOI: 10.1158/1078-0432.CCR-15-2903ISI: 000391472400028PubMedID: 26957556OAI: oai:DiVA.org:uu-315914DiVA, id: diva2:1076579
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish National Infrastructure for Computing (SNIC), b2014071Available from: 2017-02-23 Created: 2017-02-23 Last updated: 2017-11-29Bibliographically approved

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Pandzic, TatjanaLarsson, JimmyHe, LiqunKundu, SnehangshuAli, Muhammad AkhtarHellström, Anders R.Ljungström, ViktorMansouri, LarryRosenquist, RichardSjöblom, TobiasHellström, Mats

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Pandzic, TatjanaLarsson, JimmyHe, LiqunKundu, SnehangshuAli, Muhammad AkhtarHellström, Anders R.Ljungström, ViktorMansouri, LarryRosenquist, RichardSjöblom, TobiasHellström, Mats
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Experimental and Clinical OncologyScience for Life Laboratory, SciLifeLabDepartment of Immunology, Genetics and PathologyDepartment of Cell and Molecular BiologyVascular Biology
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