Editor’s Note: The 21st International Workshop on Chronic Lymphocytic Leukemia (iwCLL 2025) was held from September 12–15, 2025, in Kraków, Poland. As the premier global academic event dedicated to chronic lymphocytic leukemia (CLL), iwCLL convenes every two years, bringing together leading experts and scholars in hematologic oncology to discuss cutting-edge advances in CLL research and treatment—driving both academic innovation and clinical transformation. At this year’s meeting, Dr. Alba Garrote-de-Barros from the lab of Molecular bases of hematological tumors at Universidad Complutense de Madrid and Hospital Universitario 12 de Octubre (Madrid, Spain) presented an oral abstract (Abstract No. 1023) investigating the clinical and biological impact of MYC overexpression in CLL with or without TP53 dysfunction. Her study offers new insights into optimizing treatment strategies for these distinct patient subgroups. Oncology Frontier – Hematology Frontier conducted an exclusive interview with Dr. Garrote-de-Barros to explore the key findings and their translational significance.Oncology Frontier – Hematology Frontier:
Your study suggests that MYC overexpression correlates with worse prognosis in TP53 wild-type patients, while MYC overexpression in TP53-affected patients does not show significant prognostic differences. How do you think the role of MYC overexpression differs in the context of different TP53 statuses? What insights does this provide for personalized treatment strategies in clinical practice?
Dr. Alba Garrote-de-Barros: Our research demonstrates that, in the context of wild-type TP53, MYC overexpression is significantly associated with poorer prognosis compared to patients with low MYC expression, resulting in less favorable clinical outcomes. However, in the context of TP53 mutations, MYC overexpression does not appear to significantly impact prognosis. Similar findings were observed in our cellular models. This may be attributed to the inherently aggressive molecular characteristics conferred by TP53 mutations in leukemia cells, which likely overshadow the potential effects of MYC overexpression. This finding holds significant implications for clinical practice, particularly for patients with wild-type TP53. Although this patient group generally exhibits a better prognosis than those with TP53 mutations, there is notable heterogeneity within this cohort. Therefore, more refined stratification studies are needed for wild-type TP53 patients to further identify genetic markers associated with adverse prognosis, providing a foundation for risk assessment and personalized treatment strategies.
Oncology Frontier – Hematology Frontier:
Your study shows that MYC overexpression induces dysregulation of several biological pathways, including cell cycle regulation and DNA repair pathways, in CLL cell lines. How do you think these dysregulated pathways contribute to the progression of CLL, especially in the context of Richter transformation?
Dr. Alba Garrote-de-Barros: We observed that MYC overexpression is closely associated with gene dysregulation and the enrichment of specific signaling pathways. In patients with wild-type TP53, MYC overexpression primarily upregulates and enriches the AKT pathway, whereas in patients with TP53 mutations, it leads to the enrichment of DNA repair pathways. Based on this, we hypothesize that MYC overexpression combined with TP53 disruption may exert a dual effect—promoting cell proliferation and increasing genomic instability—which could be linked to disease progression and Richter transformation. However, in patients with TP53 mutations, MYC overexpression does not appear to significantly impact on time to first treatment or overall survival. This result was unexpected, as we initially hypothesized that MYC overexpression coupled with TP53 disruption would lead to a worse prognosis. It should be noted, however, that the MYC transcription levels measured were obtained from pretreatment samples. During treatment or disease evolution, subclones with higher MYC expression may be selected, or the MYC expression levels in existing subclones may increase, ultimately leading some patients initially classified as having low MYC expression to transition to high MYC expression. Furthermore, existing studies indicate that MYC alterations and amplifications are frequently observed in cells undergoing Richter transformation, often accompanied by TP53 disruption. This mechanism may explain why we did not observe the anticipated adverse prognostic effect in our overall survival analysis.
Oncology Frontier – Hematology Frontier:
Your research mentions that MYC overexpression leads to increased cell proliferation, especially in the TP53 wild-type background. Have you considered combining MYC overexpression with other known mechanisms of treatment resistance, such as BTK inhibitor resistance? Could this combined strategy potentially improve treatment outcomes?
Dr. Alba Garrote-de-Barros: In our study, we observed that the concurrent presence of MYC overexpression and TP53 disruption enhances the resistance of CLL cells to ibrutinib and venetoclax, which are currently the most commonly used treatments for CLL patients. Therefore, we believe it is necessary to further investigate the mechanisms underlying BTK inhibitor resistance. Additionally, we plan to explore more investigational drugs to elucidate the reasons for BTK resistance in the context of MYC overexpression and TP53 alterations. In Western blot experiments, we did not observe upregulation of the AKT-mTOR pathway, leading us to hypothesize that BTK inhibitor resistance may involve other signaling pathways rather than the PI3K-AKT-mTOR pathway. Consequently, future research will focus on potential drug targets related to MYC, DNA repair, or other signaling pathways.
Expert Profile
Dr. Alba Garrote-de-Barros Molecular bases of hematological tumors Lab at Universidad Complutense de Madrid and Hospital Universitario 12 de Octubre, Madrid, Spain Dr. Garrote-de-Barros is a researcher specializing in the molecular pathogenesis and targeted therapy of chronic lymphocytic leukemia (CLL). Her research focuses on genetic alterations driving treatment resistance, including TP53 dysfunction and MYC dysregulation, and their translational relevance for novel therapeutic strategies in hematologic malignancies.
