Molecular Signatures and Resistance Mechanisms in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma
László Tamás
Pathological and Oncological Divison
Dr. Matolcsy András
Semmelweis Egyetem Patológiai és Kísérleti Rákkutató Intézet, Arányi Lajos Terem
2026-05-07 14:30:00
Molekuláris és experimentális onkológia
Dr. Bödör Csaba
Dr. Bödör Csaba
Dr. Wiener Zoltán
Dr. Szuhai Károly
Dr. Patócs Attila
Dr. Butz Henriett
Dr. Szarvas Tibor
The advent of targeted therapies has transformed the management of B-cell malignancies such as CLL and MCL. In this era of novel, innovative treatment modalities, accurate interpretation and application of molecular prognostic and predictive biomarkers are critically important. Despite impressive clinical responses, resistance frequently emerges, resulting in poor outcomes and underscoring the urgent need to explore the underlying disease biology and the molecular mechanisms driving therapeutic resistance.
In our study focusing on CLL patients, we investigated the subclonal architecture and clinical significance of TP53 mutations in CLL using a sensitive NGS-based approach in a ‘real-world’ cohort of 901 patients. Low-burden TP53 mutations occurring as the sole alteration were detected in 39% (62/158) of mutated cases. Patients with low-burden TP53 mutations exhibited a significantly shorter time to first treatment compared to those with wild-type TP53. Our findings extend current understanding of the prevalence, clonal composition, and clinical consequences of low-burden TP53 mutations in CLL.
In our study focusing on double-resistant MCL patients, post-treatment samples showed more CNAs than pre-treatment samples (p = 0.039). Early BTKi progressors harbored CNAs in NOTCH1, TRAF2, BIRC2, BIRC3, and ATM, while two of three venetoclax-resistant patients had 9p21.3 deletions. In one case, 9p21.3 loss persisted throughout the disease course, with acquired SMARCA4 and DLC1 deletions at relapse, highlighting their potential role in therapy resistance.
In summary, our studies substantially add to the current knowledge of molecular biomarkers in these B-cell malignancies. As the prognostic or potential predictive significance of TP53 alterations becomes increasingly recognized in the era of targeted therapies in CLL, our findings on low-burden variants may hold substantial clinical relevance. We also provided novel evidence regarding the molecular background of venetoclax-resistance in MCL. Using lcWGS, an innovative genome-wide approach, our study revealed novel putative primary and acquired resistance mechanisms in BTKi and venetoclax double-resistant MCL patients.
