The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
Nature communications - 8(2017), 1 vom: 19. Dez., Seite 2185 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Landau, Dan A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.10.2018 Date Revised 13.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-017-02329-y |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM279234783 |
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| 100 | 1 | |a Landau, Dan A |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy |
| 264 | 1 | |c 2017 | |
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| 500 | |a Date Completed 01.10.2018 | ||
| 500 | |a Date Revised 13.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, N.I.H., Intramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Piperidines |2 NLM | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
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| 700 | 1 | |a Wiestner, Adrian |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Catherine J |e verfasserin |4 aut | |
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