B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric hematological malignancy. While advances in modern medicine have significantly improved survival – especially in children– treatment resistance, relapse, and refractory disease remain major challenges, highlighting the complexities in treating B-ALL and the need for ongoing research and development of novel therapeutic strategies.

Our lab previously demonstrated that the SWI/SNF chromatin remodeling complex subunit SMARCD1 is essential for the development of the lymphoid lineage, as its inactivation in the adult hematopoietic system leads to lymphopenia while sparing the myeloid and erythroid lineages (Priam et al., Developmental Cell, 2024). In this study, we identify SMARCD1 as an essential gene in B-ALL. Specifically, SMARCD1 inactivation in B-ALL cell lines and patient-derived xenograft (PDX) cells results in profound defects in cellular proliferation and survival. However, the molecular mechanisms underlying its oncogenic role in this context remain to be elucidated.

The SMARCD1 subunit does not directly bind DNA or chromatin; instead, it is recruited to specific genomic loci through interactions with various co-factors, including the tumor suppressor protein p53. Interestingly, although p53 is somatically mutated in over half of human cancers, it remains wild-type (WTp53) in approximately 75% of newly diagnosed adult ALL cases and 97–98% of pediatric ALL cases at diagnosis (Stengel et al., Blood, 2014, Leukemia, 2017). Given that genetic instability is a hallmark of cancer, understanding why some malignancies retain WTp53 despite its tumor-suppressive functions is a key question with important therapeutic implications. Emerging evidence suggests WTp53 may promote oncogenic functions in specific cancer contexts by regulating metabolic plasticity and pro-survival signaling pathways.

In B-ALL cell lines, we confirmed a biochemical interaction between SMARCD1 and WTp53 using coimmunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC). We further demonstrated that the SMARCD1-dependent B-ALL cell lines are also reliant on WTp53, as p53 inactivation impairs proliferation and survival to a similar extent as SMARCD1 depletion. Notably, co-depletion of both proteins did not rescue the proliferative defect, suggesting a cooperative role in driving leukemia progression. Importantly, this dependency was not observed in p53-proficient non-hematopoietic cell lines, supporting a context-specific oncogenic role for this SMARCD1-WTp53 axis in B-ALL.

To explore how the SMARCD1-WTp53 axis drives B-ALL progression, we performed bulk RNA sequencing of B-ALL cells depleted of either SMARCD1 or TP53. Differential expression and gene set enrichment analyses (GSEA) revealed overlapping downregulation of pathways linked to proliferation and metabolism, including hypoxia, fatty acid metabolism, glycolysis, and mTORC1 signaling. Notably, key metabolic enzymes and regulators - such as GLUT4/SLC2A4, HK2, and SDHA- were consistently downregulated upon loss of either SMARCD1 or TP53. These transcriptomic changes were supported by Seahorse XF metabolic flux analyses, which confirmed reduced metabolic activity in SMARCD1- and TP53-depleted B-ALL cells. Cleavage Under Targets and Tagmentation (CUT&Tag) analyses further showed that SMARCD1 and WTp53 predominantly co-occupy the promoter regions of common target genes. Ongoing studies aim to elucidate their cooperative roles in modulating chromatin accessibility and promoter/enhancer function at these loci.

Collectively, our findings identify the SMARCD1-WTp53 axis as a key regulator of metabolic programming in B-ALL, supporting a high metabolic state and rapid proliferation through control of a distinct oncogenic transcriptional program. This work has important therapeutic implications, highlighting the potential of targeting chromatin-metabolism crosstalk in B-ALL via disruption of the SMARCD1-WTp53 axis. Furthermore, this study reveals a context-dependent oncogenic role for WTp53, emphasizing the need for precision therapies tailored to p53 status - whether by activating WTp53 or restoring its function in p53-mutant cancers.

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2025
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