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The complex interplay between cell-intrinsic and cell-extrinsic factors driving the evolution of chronic lymphocytic leukemia
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 Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
2015 (English)In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 34, 22-35 p.Article, review/survey (Refereed) Published
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Text
Abstract [en]

With the advent of next-generation sequencing, the mutational landscape of chronic lymphocytic leukemia (CLL) was rapidly unraveled with the discovery of recurrently mutated genes affecting key signaling pathways. Although the majority of these mutations are relatively infrequent at diagnosis (at least at the population-level) they tend to accumulate as the disease progresses or at relapse. Besides TP53 aberrations, several of these newly mutated genes have consistently been linked to shorter time to progression/treatment and poor overall survival (e.g. NOTCH1, SF3B1, BIRC3). These findings coupled with the diverse (sub)clonal evolution trajectory followed by CLL cells, at least in treated patients, alludes to their role as major subclonal driver events for disease progression. Together with the dependence of CLL cells on B-cell receptor (BcR) signaling and antigen stimulation, this reveals a disease within which both cell-intrinsic and cell-extrinsic factors conspire to fuel leukemogenesis, and we have only recently begun to understand their intricate interplay. This was further highlighted with the efficiency of new targeted therapy interfering with the microenvironment and in particular with BcR signaling. Further investigations will now be paramount in order to individualize treatment, to define optimal combination therapies and to integrate molecular characterization for response prediction, in this, as yet, incurable disease.

Place, publisher, year, edition, pages
2015. Vol. 34, 22-35 p.
Keyword [en]
Chronic lymphocytic leukemia, Next-generation sequencing, Immunogenetics, Clonal evolution, B-cell receptor signaling
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-269148DOI: 10.1016/j.semcancer.2015.04.009ISI: 000363077500004PubMedID: 25963298OAI: oai:DiVA.org:uu-269148DiVA: diva2:882300
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2015-12-14 Created: 2015-12-14 Last updated: 2017-12-01Bibliographically approved

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Rosenquist, Richard Brandell

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