Your browser doesn't support javascript.
loading
Single-cell sequencing demonstrates complex resistance landscape in CLL and MCL treated with BTK and BCL2 inhibitors.
Thompson, Ella R; Nguyen, Tamia; Kankanige, Yamuna; Markham, John F; Anderson, Mary Ann; Handunnetti, Sasanka M; Thijssen, Rachel; Yeh, Paul Sung-Hao; Tam, Constantine S; Seymour, John F; Roberts, Andrew W; Westerman, David A; Blombery, Piers.
Afiliación
  • Thompson ER; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • Nguyen T; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
  • Kankanige Y; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • Markham JF; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • Anderson MA; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
  • Handunnetti SM; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.
  • Thijssen R; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
  • Yeh PS; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.
  • Tam CS; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; and.
  • Seymour JF; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia.
  • Roberts AW; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.
  • Westerman DA; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; and.
  • Blombery P; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.
Blood Adv ; 6(2): 503-508, 2022 01 25.
Article en En | MEDLINE | ID: mdl-34861696
The genomic landscape of resistance to targeted agents (TAs) used as monotherapy in chronic lymphocytic leukemia (CLL) is complex and often heterogeneous at the patient level. To gain insight into the clonal architecture of acquired genomic resistance to Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL2) inhibitors in CLL, particularly in patients carrying multiple resistance mutations, we performed targeted single-cell DNA sequencing of 8 patients who developed progressive disease (PD) on TAs (either class). In all cases, analysis of single-cell architecture revealed mutual exclusivity between multiple resistance mutations to the same TA class, variable clonal co-occurrence of multiple mutations affecting different TAs in patients exposed to both classes, and a phenomenon of multiple independent emergences of identical nucleotide changes leading to canonical resistance mutations. We also report the first observation of established BCL2 resistance mutations in a patient with mantle cell lymphoma (MCL) following PD on sequential monotherapy, implicating BCL2 as a venetoclax resistance mechanism in MCL. Taken together, these data reveal the significant clonal complexity of CLL and MCL progression on TAs at the nucleotide level and confirm the presence of multiple, clonally independent, mechanisms of TA resistance within each individual disease context.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Linfocítica Crónica de Células B / Linfoma de Células del Manto / Antineoplásicos Límite: Adult / Humans Idioma: En Revista: Blood Adv Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Linfocítica Crónica de Células B / Linfoma de Células del Manto / Antineoplásicos Límite: Adult / Humans Idioma: En Revista: Blood Adv Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos