Mentor Name: Christian Hurtz

The Hurtz laboratory is focused on identifying new treatment strategies for children with high-risk acute lymphoblastic leukemia (ALL). While overall survival rates for pediatric ALL have significantly improved over the past decade, children diagnosed with KMT2A-rearranged (KMT2A-R) or CRLF2-R (Ph-like) ALL still face poor clinical outcomes. SMARCA4, a key component of the SWI/SNF chromatin-remodeling complex, plays a critical role in regulating gene expression. It has been extensively studied in solid tumors—such as lung cancer, ovarian cancer, and rhabdoid tumors—where SMARCA4 mutations and alterations are associated with aggressive behavior and poor prognosis. Although SMARCA4 is vital for B-cell development, its specific role in B-cell acute lymphoblastic leukemia (B-ALL) remains largely unexplored. To address this gap, we combined single-cell DNA sequencing with meta-analyses of Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) data from 1,717 children with B-ALL. Our results revealed that, in contrast to solid tumors, the mutation frequency of SMARCA4 in pediatric B-ALL is very low (0.35%). This suggests that non-mutated SMARCA4 may be critical for B-ALL pathogenesis. Further analysis using the DepMAP portal showed that certain B-ALL cells depend heavily on SMARCA4, implying that SMARCA4 inhibition could serve as a potential therapeutic strategy. An initial survival analysis of 207 children from the COG trial P9906 indicated no significant impact of SMARCA4 expression on overall outcomes. However, a closer look at high-risk subtypes revealed a complex relationship: 1) Ph-like B-ALL: Higher SMARCA4 expression correlated with poorer outcomes, and 2) KMT2A-R ALL: Higher SMARCA4 expression was paradoxically linked to better outcomes. Western blot analyses confirmed that SMARCA4 expression was significantly elevated in Ph-like ALL compared with KMT2A-R ALL, leading us to hypothesize that Ph-like ALL (but not KMT2A-R ALL) depends on high SMARCA4 levels. Testing two newly developed SMARCA4 inhibitors (BRM014 and FHD-286) supported this hypothesis: Ph-like cells were highly sensitive to these inhibitors, while KMT2A-R cells were resistant. Our ongoing research seeks to further validate the role of SMARCA4 in Ph-like ALL and to explore its underlying regulatory mechanisms. In particular, we plan to test whether a dual treatment strategy, combining SMARCA4 inhibition with chemotherapy, can synergistically kill Ph-like ALL cell lines and patient-derived xenograft (PDX) models.