The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy.
Dan A LandauClare SunDaniel RosebrockSarah E M HermanJoshua FeinMariela SivinaChingiz UnderbayevDelong LiuJulia HoellenriegelSarangan RavichandranMohammed Z H FarooquiWandi ZhangCarrie CibulskisAsaf ZviranDonna S NeubergDimitri LivitzIvana BozicIgnaty LeshchinerGad A GetzJan A BurgerAdrian WiestnerCatherine J WuPublished in: Nature communications (2017)
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.
Keyphrases
- chronic lymphocytic leukemia
- drug resistant
- cell cycle
- genome wide
- cell proliferation
- end stage renal disease
- newly diagnosed
- single cell
- multidrug resistant
- gene expression
- acinetobacter baumannii
- emergency department
- chronic kidney disease
- ejection fraction
- cancer therapy
- rna seq
- photodynamic therapy
- tyrosine kinase
- peritoneal dialysis
- transcription factor
- radiation therapy
- copy number
- dna methylation
- mesenchymal stem cells
- locally advanced
- cell therapy
- drug induced