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NFATc1 and NFATc2 regulate glucocorticoid resistance in pediatric T-cell acute lymphoblastic leukemia through modulation of cholesterol biosynthesis and the WNT/β-catenin pathway

ABSTRACT: he glucocorticoid (GC) resistance onset in pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) patients remains one of the biggest challenges in current cancer treatment. The mechanisms driving this resistance are still not fully understood, making it difficult to predict patient outcomes and to develop effective therapies. Our study uncovered critical insights into the biological processes underlying GC resistance, offering potential breakthroughs for future treatments. Building on our previous research on LCK kinase hyperactivation in GC-resistant T-ALL patients, we have now delved deeper into the LCK downstream NFAT transcription factor family's contribution to GC resistance. We discovered that, even at the time of diagnosis, GC resistant T-ALL patients exhibit an intrinsic low glucocorticoid receptor (GR) activity coupled with high NFATc1 and NFATc2 ones. This dysregulation creates a roadblock to effective GC therapy. Indeed, in the absence of either NFATc1 or NFATc2, the normal transcriptional activity of GR is restored, re-sensitizing the leukemia cells to dexamethasone treatment both in vitro and in vivo. This suggests that NFATc1 and NFATc2 are central to driving GC resistance, as they directly regulate crucial pathways like cholesterol biosynthesis and WNT/β-catenin signaling. The identification of NFAT transcription factors as key players in leukemia therapy resistance offers a promising target for future therapeutic strategies, potentially transforming the way we approach treatment for these challenging conditions or autoimmune disorders where glucocorticoids are a cornerstone of treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253999 | GEO | 2025/11/28

REPOSITORIES: GEO

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Project description:LC-MS data and DIA-NN search files relating to: PU.1 Eviction at Lymphocyte-Specific Chromatin Domains Mediates Glucocorticoid Response in Acute Lymphoblastic Leukemia. Abstract: The epigenetic landscape plays a critical role in the onset and evolution of various malignancies, but its therapeutic utility remains underutilized. Glucocorticoids are an essential part of many multi-agent treatment regimens for lymphoid malignancies. However, the emergence of glucocorticoid resistance is a significant barrier to cure, which is in part due to epigenetic alterations, including aberrant chromatin accessibility and hypermethylation at lymphocyte-specific glucocorticoid-response elements (GREs). To gain a deeper understanding of regulatory mechanisms leading to these epigenetic alterations, we conducted a multi-omics study, including chromosome conformation capture sequencing (HiC), to examine changes in the 3D genome structure following the in vivo treatment of acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) with glucocorticoid. We found that glucocorticoid treatment led to distinct patterns of topologically associated domains (TADs) in glucocorticoid sensitive compared to resistant PDXs. Furthermore, we show that these TADs were primed by the development-related pioneer transcription factor PU.1, which extensively interacts with the glucocorticoid receptor (GR) exclusively in glucocorticoid-sensitive ALL PDXs. An integrative analysis of rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) and ChIP-seq revealed that PU.1 binding was associated with lymphocyte-specific activation of GREs and GRE-interacting super-enhancers. The PU.1-associated TADs modulated epigenetic marks, and particularly the eviction of PU.1 promoted GR binding and the expression of signature genes, including BIM, ZBTB16 and RASA1, mediating glucocorticoid-induced apoptosis in ALL. These findings were phenocopied using a PU.1 inhibitor DB2313 to restore glucocorticoid sensitivity in ALL. Taken together, this study identified a new epigenetic pathway integrating PU.1 priming and PU.1-GR interaction which ultimately leads to PU.1 eviction in ALL. This pathway provides the first link between the activity of a lineage-specific transcription factor and epigenetic modulators mediating the response to glucocorticoids and thus offers a new avenue to translate fundamental epigenetic research into the clinic.

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NFATc1 and NFATc2 regulate glucocorticoid resistance in pediatric T-cell acute lymphoblastic leukemia through modulation of cholesterol biosynthesis and the WNT/β-catenin pathway

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