Dissecting clonal hematopoiesis in the myeloid compartment of chronic lymphocytic leukemia and Richter transformation.

ABSTRACT: The clinical and biological significance of clonal hematopoiesis (CH) has not been investigated in the myeloid compartment of chronic lymphocytic leukemia (CLL). By studying 488 newly diagnosed CLL through CAPP-seq using a 28-gene panel on granulocyte genomic DNA (gDNA), CH occurred in 231 (47.3%) patients. Cell sorting of cases that never developed Richter transformation (RT) confirmed that CH mutations, including CH-related TP53 mutations, were restricted to the myelomonocytic compartment and absent in CLL cells, as also documented by single-cell DNA sequencing. CH associated with shorter overall survival (OS) (hazard ratio [HR] 1.36, 95% CI 1.04-1.77, P = 0.023); specifically, TET2 mutations independently predicted inferior OS (HR 1.62, 95% CI 1.15-2.28, P = 0.01) after adjusting for age and for CLL-related prognostic biomarkers, namely IGHV and TP53 status. Regarding therapy-related toxicities, CH correlated with a higher incidence of Grade ≥ 3 neutropenia (P = 0.004) after venetoclax-based regimens. Sequential samples (n = 57) analysis showed that Bruton tyrosine kinase (BTK) and BCL2 inhibitors do not induce CH expansion, which was instead driven by chemotherapy. CH is significantly associated with a higher risk of second hematological malignancies only in chemo-exposed patients. Single-cell RNA sequencing of seven CH+ and six CH- CLL revealed that the T-cell compartment of CH+ patients exhibits a less exhausted phenotype, documented by lower expression of TOX, the master regulator of T-cell exhaustion, and a higher pro-inflammatory profile. CH also influenced RT, since CH ASXL1 mutations independently associated with higher RT risk (HR 11.19, 95% CI 4.09-30.62, P < 0.001). Overall, CH in CLL impacts survival, therapeutic toxicity, and transformation risk while also influencing the T-cell immune compartment.

SUBMITTER: Cosentino C 

PROVIDER: S-EPMC12907972 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature