Biology subjects

Dzama-Karels, M.

Publications and source records attributed to Dzama-Karels, M..

3 recordsLinked to original sources

bioRxiv2026

Loss of cBAF Complex Confers Sorafenib Resistance in Liver Cancer

Sorafenib resistance limits the clinical benefit of first-line therapy in hepatocellular carcinoma (HCC), yet the epigenetic mechanisms underlying this resistance remain poorly understood. Using a chromatin-focused CRISPR/Cas9 dropout screen in HepG2 cells, we identified subunits of the canonical BAF (cBAF) complex -- ARID1A, ARID1B, and SMARCC1 -- as functional drivers of sorafenib resistance, while loss of the PBAF-specific subunit ARID2 had no effect, implicating cBAF specifically rather than SWI/SNF broadly. ARID1A and ARID1B mutations are associated with significantly worse overall survival in TCGA hepatocellular carcinoma cohorts. To define the underlying mechanism, we performed CUT&RUN profiling and RNA-seq in ARID1B-knockout HepG2 cells under sorafenib treatment. ARID1B loss triggered selective depletion of H3K4me3 and H3K27ac at 74 cBAF-dependent regulatory elements, 72% of which were directly occupied by ARID1B in wild-type cells. These sites were enriched for FOXA1 and HNF4 motifs, consistent with disruption of hepatocyte lineage regulatory chromatin. Direct profiling in HLF hepatocellular carcinoma cells confirmed that 179 FOXA1 binding sites were lost specifically under the combined perturbation of ARID1B loss and sorafenib treatment, with neither condition alone sufficient to drive this effect. Transcriptionally, ARID1B loss induced epithelial-mesenchymal transition programs and suppressed MYC targets, E2F targets, and mTORC1 signaling. These findings define a cBAF-FOXA1 regulatory axis that maintains hepatocyte lineage identity under kinase inhibitor stress, and whose disruption drives epigenetic reprogramming toward a mesenchymal drug-tolerant state. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/731725v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1ce2352org.highwire.dtl.DTLVardef@70f2f5org.highwire.dtl.DTLVardef@15ee96borg.highwire.dtl.DTLVardef@2e7edd_HPS_FORMAT_FIGEXP M_FIG C_FIG

Cancer Biology↗

bioRxiv2026

Menin-Inhibition Sensitizes Acute Myeloid Leukemia to CLEC12A-Directed CAR Cell Therapy

Menin inhibitors targeting the Menin-KMT2A chromatin complex have emerged as highly selective therapies for KMT2A-rearranged (KMT2A-r) and NPM1-mutated (NPM1mut) acute myeloid leukemia (AML), with recent regulatory approval and increasing interest in combination strategies. In contrast, CAR cell therapies have not yet been successfully established for AML. Here, we show that menin-inhibition primes KMT2A-r and NPM1mut AML for CAR-based targeting by inducing robust and uniform expression of the myeloid antigen CLEC12A (CLL-1). Menin inhibitors did not impair T or NK cell viability, phenotype, or effector function. We engineered second-generation CLEC12A-directed CAR T cells that efficiently eliminated CLEC12A-positive AML. Across in vitro systems and xenograft models, the combination therapy consistently outperformed either monotherapy, resulting in profound disease control and significantly prolonged survival, with evidence of near-complete leukemia eradication in vivo. These findings support epigenetic priming with menin inhibitors to enhance CLEC12A-directed CAR cell-therapy in these AML subtypes. SignificanceMenin inhibitors, now approved for AML treatment, induce the immune target CLEC12A in NPM1mut and KMT2A-r AML subtypes and sensitize AML cells to CLEC12A-directed CAR T cells without compromising immune function. As CLEC12A-CARs are already in clinical testing, this combination is immediately actionable for clinical investigation.

cancer biology↗

bioRxiv2025

Menin-MLL1 complex cooperates with NF-Y to promote HCC survival

Identification of new therapeutic targets in hepatocellular carcinoma (HCC) remains critical. Chromatin regulating complexes are frequently mutated or aberrantly expressed in HCC, suggesting dysregulation of chromatin environments is a key feature driving liver cancer. To investigate whether the altered chromatin state in HCC cells could be targeted, we designed and utilized an epigenome-focused CRISPR library that targets genes involved in chromatin regulation. This focused approach allowed us to test multiple HCC cell lines in both 2D and 3D growth conditions, which revealed striking differences in the essentiality of genes involved in ubiquitination and multiple chromatin regulators vital for HCC cell survival in 2D but whose loss promoted growth in 3D. We found the core subunits of the menin-MLL1 complex among the strongest essential genes for HCC survival in all screens and thoroughly characterized the mechanism through which the menin-MLL1 complex promotes HCC cell growth. Inhibition of the menin-MLL1 interaction led to global changes in occupancy of the complex with concomitant decreases in H3K4me3 and expression of genes involved in PI3K/AKT/mTOR signaling pathway. Menin inhibition affected chromatin accessibility in HCC cells, revealing that increased chromatin accessibility at sites not bound by menin-MLL1 was associated with the recruitment of the pioneer transcription factor complex NF-Y. A CRISPR/Cas9 screen of chromatin regulators in the presence of menin inhibitor SNDX-5613 revealed a significantly increased cell death when combined with NFYB knockout. Together these data show that menin-MLL1 is necessary for HCC cell survival and cooperates with NF-Y to regulate oncogenic gene transcription.

cancer biology↗