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Nat Commun DOI:10.1038/s41467-017-02329-y

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

Publication TypeJournal Article
Year of Publication2017
AuthorsLandau, DA, Sun, C, Rosebrock, D, Herman, SEM, Fein, J, Sivina, M, Underbayev, C, Liu, D, Hoellenriegel, J, Ravichandran, S, Farooqui, MZH, Zhang, W, Cibulskis, C, Zviran, A, Neuberg, DS, Livitz, D, Bozic, I, Leshchiner, I, Getz, G, Burger, JA, Wiestner, A, Wu, CJ
JournalNat Commun
Date Published2017 Dec 19

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.


Alternate JournalNat Commun
PubMed ID29259203
PubMed Central IDPMC5736707
Grant ListU10 CA180861 / CA / NCI NIH HHS / United States
R01 CA182461 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
K01 ES025431 / ES / NIEHS NIH HHS / United States
R01 CA184922 / CA / NCI NIH HHS / United States