In the third week of PLOS Medicine's ongoing special issue on cancer genomics, principal investigator Jules Meijerink of the Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands and colleagues seek to identify mechanisms underlying treatment resistance in children with T-cell acute lymphoblastic leukemia (T-ALL) by combining genomic DNA sequencing and chromosomal copy-number analyses, and suggest a new approach to therapy.
Treatment of childhood leukemia has improved markedly in recent decades, with long-term cure achieved in most patients who have access to modern, highly intensive treatment regimens. However, some patients develop resistance to the steroid drugs which are a key part of combination chemotherapy treatments, which results in poor clinical outcomes. As described in their Research Article, Meijerink and colleagues studied genetic changes in leukemic cells from pediatric T-ALL patients before treatment. The researchers found specific gene mutations affecting signaling inside cells, involving the interleukin 7 receptor and downstream molecules, that were associated with steroid resistance and adverse clinical outcome. Drugs designed to target individual signaling proteins were able to restore steroid sensitivity to primary leukemic cells from patients.
Discussing the research in an accompanying Perspective article, Steven Goossens and Pieter Van Vlierberghe conclude that "inhibition of MEK-ERK or PI3K/AKT/mTOR signaling could enhance steroid sensitivity in T-ALL and potentially improve patient outcomes, a notion that warrants investigation in future prospective clinical trials."
Funding: YL was funded by Stichting Kinderen Kankervrij (https://www.kika.nl; KiKa-2010-082). KC-B and WKS were funded by Stichting Kinderen Kankervrij (https://www.kika.nl; KiKa-2008-029, KiKa-2013-116). EMV was funded by KWF Kanker Bestrijding (https://www.kwf.nl; EMCR-KWF-2010-4691). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: RCB and GJRZ are founders and shareholders of Netherlands Translational Research Center B.V. The other authors have declared that no competing interests exist.
Citation: Li Y, Buijs-Gladdines JGCAM, Canté-Barrett K, Stubbs AP, Vroegindeweij EM, Smits WK, et al. (2016) IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study. PLoS Med 13(12): e1002200. doi:10.1371/journal.pmed.1002200
Department of Pediatric Oncology/Hematology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Bioinformatics, Erasmus Medical Center, Rotterdam, The Netherlands
Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
Research Institute Children's Cancer Center Hamburg, Hamburg, Germany
Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Co-operative Study Group for Childhood Acute Lymphoblastic Leukemia, Hamburg, Germany
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Netherlands Translational Research Center, Oss, The Netherlands
IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002200
Funding: The authors received no funding for this work.
Competing Interests: The authors have declared that no competing interests exist.
Citation: Goossens S, Van Vlierberghe P (2016) Overcoming Steroid Resistance in T Cell Acute Lymphoblastic Leukemia. PLoS Med 13(12): e1002208. doi:10.1371/journal.pmed.1002208
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium
Cancer Research Institute Ghent (CRIG), Ghent, Belgium
IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002208