Biology subjects

Malgulwar, P. B.

Publications and source records attributed to Malgulwar, P. B..

3 recordsLinked to original sources

bioRxiv2025

ATRX Loss Predicts Poor Outcomes and Reveals a Therapeutic Vulnerability to TEAD Inhibition in Soft Tissue Sarcomas

ATRX is one of the most frequently altered genes in sarcoma and encodes an ATP-dependent chromatin remodeler implicated in maintaining heterochromatin. However, ATRX alterations have not been leveraged for sarcoma treatment. We observed loss of ATRX protein in 14% of soft tissue leiomyosarcoma (STLMS, n =127), 53% of uterine leiomyosarcoma (ULMS, n = 95), 37% of undifferentiated pleomorphic sarcoma (UPS, n = 82), and 8% of dedifferentiated liposarcoma (DDLPS, n = 84). ATRX loss was associated with significantly worse outcomes in ULMS, UPS, and DDLPS. ATRX knockout in sarcoma cells increased proliferation in cooperation with TP53 deletion. ATRX knockout led to chromatin de-repression and enrichment of PRDM4 and NFIX transcription factor (TF) motifs. PRDM4 and NFIX knockdown in ATRX-mutant sarcoma lines resulted in reduced proliferation and invasion suggesting epistatic relationship. Consistent with the known functional relationship between PRMD4 and YAP1, we observed that ATRX/TP53 KO cells were more sensitive to the TEAD inhibitor VT103 compared to TP53 KO and ATRX WT controls. Overall, our results identify ATRX loss as a prognostic factor of worse outcomes, implicate the ATRX-PRDM4-YAP1 axis as a novel underlying mechanism, and suggest use of TEAD inhibition as a potential therapeutic strategy for ATRX-deficient sarcomas. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=45 SRC="FIGDIR/small/689992v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@a759ecorg.highwire.dtl.DTLVardef@100c580org.highwire.dtl.DTLVardef@1a675c9org.highwire.dtl.DTLVardef@17f1f91_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX knockout glioma models in the presence and absence of the IDH1R132H mutation. ATRX-deficient glioma cells were sensitive to dsRNA-based innate immune agonism and exhibited impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1R132Hdampened baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1R132H inhibition. IDH1R132H co-expression did not interfere with the ATRX KO-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytoma.

cancer biology↗

bioRxiv2023

Sirtuin 2 inhibition modulates chromatin landscapes genome- wide to induce senescence in ATRX-deficient malignant glioma

Inactivating mutations in ATRX characterize large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped. We utilized integrated mulit-omics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanim(s). CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (Sirt2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. Sirt2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroprogenitor cells (mNPCs) and impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs). While effects on cellular proliferation in these contexts were more modest, markers of senescence significantly increased, suggesting that Sirt2 inhibition promotes terminal differentiation in ATRX-deficient glioma. These phenotypic effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to Sirt2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon Sirt2 inhibition. Finally, Sirt2 inhibition impaired growth and increased senescence in ATRX-deficient GSCs in vivo. Our findings indicate that Sirt2 inhibition selectively targets ATRX-deficient gliomas through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/523324v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1d1c7cborg.highwire.dtl.DTLVardef@19421fcorg.highwire.dtl.DTLVardef@433aaaorg.highwire.dtl.DTLVardef@1c07f72_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryOur study demonstrates that SIRT2 inhibition promotes senescence in ATRX-deficient glioma model systems through global epigenomic remodeling, impacting key downstream transcriptional profiles.

cancer biology↗