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Nat Commun. 2017 Dec 19;8(1):2185. doi: 10.1038/s41467-017-02329-y.

The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy.

Author information

1
New York Genome Center, New York, NY, 10013, USA.
2
Broad Institute, Cambridge, MA, 02142, USA.
3
Meyer Cancer Center & Institute of Computational Biomedicine, Weill Cornell Medicine, New York, NY, 10065, USA.
4
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
5
Sackler Medical School, Tel Aviv University, Tel Aviv, 6997801, Israel.
6
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
7
Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc, Frederick, MD, 21701, USA.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
9
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
10
Department of Applied Mathematics, University of Washington, Seattle, WA, 98195, USA.
11
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA. wiestnea@nhlbi.nih.gov.
12
Broad Institute, Cambridge, MA, 02142, USA. cwu@partners.org.
13
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. cwu@partners.org.
14
Harvard Medical School, Boston, MA, 02215, USA. cwu@partners.org.

Abstract

Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo-immunotherapy to targeted agents. To define the evolutionary dynamics induced by targeted therapy in CLL, we perform serial exome and transcriptome sequencing for 61 ibrutinib-treated CLLs. Here, we report clonal shifts (change >0.1 in clonal cancer cell fraction, Q < 0.1) in 31% of patients during the first year of therapy, associated with adverse outcome. We also observe transcriptional downregulation of pathways mediating energy metabolism, cell cycle, and B cell receptor signaling. Known and previously undescribed mutations in BTK and PLCG2, or uncommonly, other candidate alterations are present in seventeen subjects at the time of progression. Thus, the frequently observed clonal shifts during the early treatment period and its potential association with adverse outcome may reflect greater evolutionary capacity, heralding the emergence of drug-resistant clones.

PMID:
29259203
PMCID:
PMC5736707
DOI:
10.1038/s41467-017-02329-y
[Indexed for MEDLINE]
Free PMC Article

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