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Early reappearance of intraclonal proliferative subpopulations in ibrutinib-resistant chronic lymphocytic leukemia.
- Source :
-
Leukemia [Leukemia] 2024 Aug; Vol. 38 (8), pp. 1712-1721. Date of Electronic Publication: 2024 Jun 24. - Publication Year :
- 2024
-
Abstract
- The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib represents an effective strategy for treatment of chronic lymphocytic leukemia (CLL), nevertheless about 30% of patients eventually undergo disease progression. Here we investigated by flow cytometry the long-term modulation of the CLL CXCR4 <superscript>dim</superscript> /CD5 <superscript>bright</superscript> proliferative fraction (PF), its correlation with therapeutic outcome and emergence of ibrutinib resistance. By longitudinal tracking, the PF, initially suppressed by ibrutinib, reappeared upon early disease progression, without association with lymphocyte count or serum beta-2-microglobulin. Somatic mutations of BTK/PLCG2, detected in 57% of progressing cases, were significantly enriched in PF with a 3-fold greater allele frequency than the non-PF fraction, suggesting a BTK/PLCG2-mutated reservoir resident within the proliferative compartments. PF increase was also present in BTK/PLCG2-unmutated cases at progression, indicating that PF evaluation could represent a marker of CLL progression under ibrutinib. Furthermore, we evidence different transcriptomic profiles of PF at progression in cases with or without BTK/PLCG2 mutations, suggestive of a reactivation of B-cell receptor signaling or the emergence of bypass signaling through MYC and/or Toll-Like-Receptor-9. Clinically, longitudinal monitoring of the CXCR4 <superscript>dim</superscript> /CD5 <superscript>bright</superscript> PF by flow cytometry may provide a simple tool helping to intercept CLL progression under ibrutinib therapy.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Cell Proliferation drug effects
Phospholipase C gamma genetics
Disease Progression
Protein Kinase Inhibitors therapeutic use
Protein Kinase Inhibitors pharmacology
Male
Aged
Female
Middle Aged
CD5 Antigens metabolism
CD5 Antigens genetics
Adenine analogs & derivatives
Piperidines
Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell genetics
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Drug Resistance, Neoplasm genetics
Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors
Agammaglobulinaemia Tyrosine Kinase genetics
Pyrimidines therapeutic use
Pyrimidines pharmacology
Pyrazoles therapeutic use
Pyrazoles pharmacology
Receptors, CXCR4 genetics
Receptors, CXCR4 metabolism
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 38
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 38914716
- Full Text :
- https://doi.org/10.1038/s41375-024-02301-y