Biology subjects

Sasca, D.

Publications and source records attributed to Sasca, D..

5 recordsLinked to original sources

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↗

bioRxiv2024

DNMT/G9a Complex Inhibition Uncovers Epigenetic Vulnerabilities and Induces IFN-Response in Acute Myeloid Leukemia

Epigenetic dysregulation is a hallmark of Acute Myeloid Leukemia (AML), with mutations in DNA Methyltransferases (e.g., DNMT3A) being frequent and promising therapeutic targets. DNMTs form complexes with Histone Methyltransferases (HMTs), driving gene silencing loop via chromatin methylation crosstalk. However, potential connections between this DNMTs/HMTs cooperative activity and oncogenic requirements across the AML mutational spectrum remain poorly understood. Here, we demonstrate that AMLs carrying DNMT3A and Nucleophosmin (NPM1) mutations exhibit a specific epigenetic vulnerability toward a complex formed by DNMTs and G9a, a specific histone H3 Lysine 9 Methyltransferase (H3K9-HMT). Dual inhibition of DNMT/G9a restores differentiation, reduces tumor growth, and spares healthy progenitors compared to standard hypomethylating agents. Mechanistically, DNMT/G9a regulates NPM1 stability, inhibits HOXA9/MEIS1 activity, and triggers interferons (IFN) response via viral mimicry pathways by modulating hypermethylated retrotransposons. Collectively, our data unravel specific epigenetic vulnerabilities within the complex AML mutational landscape and provide a compelling rationale for the design of personalized epigenetic therapies with enhanced efficacy and safer clinical outcomes.

cancer biology↗

bioRxiv2022

HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia

HOXA9 is commonly upregulated in acute myeloid leukemia (AML), where it confers poor prognosis. Characterising the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein-SAFB. SAFB perturbation phenocopied HOXA9 knockout to decrease AML proliferation, increase differentiation and apoptosis in vitro and prolonged survival in vivo. Integrated genomic, transcriptomic and proteomic analyses further demonstrated that the HOXA9-SAFB-chromatin complex associates with NuRD and HP1{gamma} to repress the expression of factors associated with differentiation and apoptosis, including NOTCH, CEBP{delta}, S100A8, and CDKN1A. Chemical or genetic perturbation of NuRD and HP1{gamma} catalytic activity also triggered differentiation, apoptosis and the induction of these tumor-suppressive genes. Importantly, this mechanism is operative in other HOXA9-dependent AML genotypes. This mechanistic insight demonstrates active HOXA9-dependent differentiation block as a potent mechanism of disease maintenance in AML, that may be amenable to therapeutic intervention via therapies targeting the HOXA9/SAFB interface and/or NuRD and HP1{gamma} activity. Key Points- Identification of the endogenous human HOXA9 protein interactome in AML - HOXA9 forms a repressive complex with S/MAR binding protein (SAFB) that is critical for the maintenance of AML by facilitating proliferation and preventing differentiation and cell death. - The HOXA9/SAFB (H9SB) complex represses gene expression via recruitment of NuRD and HP1{gamma}.

cancer biology↗

bioRxiv2022

Acute resistance to BET inhibitors remodels compensatory transcriptional programs via p300 co-activation

Initial clinical trials with drugs targeting epigenetic modulators - such as bromodomain and extraterminal (BET) inhibitors - demonstrate modest results in acute myeloid leukemia (AML). The main reason for this involves an increased transcriptional plasticity within AML, which allows cells to escape the therapeutic pressure. To study mechanisms of resistance, we investigated immediate epigenetic and transcriptional responses following BET inhibition, and could demonstrate that BET inhibitor-mediated release of BRD4 from chromatin is accompanied by an acute compensatory feedback loop that attenuates inhibition, or even increases expression, of specific transcriptional modules. This adaptation is most marked at key AML maintenance genes and is mediated by p300, suggesting a rational therapeutic opportunity by combining BET- and p300- inhibition. p300 activity is required during all steps of adaptation. However, the transcriptional programs that p300 regulates to induce resistance to BETi differ between AML subtypes. Remarkably, in some AMLs, p300 regulates a series of transitional transcriptional patterns that allow homeostatic adjustments during earlier stages of resistance to BET-inhibitors. In consequence, p300 remains crucial throughout all stages of resistance in sensitive AML-subtypes, although its importance declines following the development of chronic resistance to BET inhibitors in some other AMLs. Altogether, our study elucidates the mechanisms that underlie an "acute" state of resistance to BET inhibition, achieved through p300 activity, and how these mechanisms remodel to become "chronic". Importantly, however, our data also suggest that a sequential treatment with BET- and p300 inhibition may prevent resistance development, thereby improving outcomes. Key pointsO_LIA mechanistic feedback to p300 enables acute tolerance to BET inhibition. C_LIO_LIp300 regulates transcriptional networks that lead to chronic resistance to BET inhibition. C_LIO_LISequential BET-, followed by p300-inhibition, is synthetically lethal in AML, and is optimally deployed during earlier stages of resistance to BET inhibitors. C_LI

cancer biology↗

bioRxiv2020

Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction

Altered transcription is a cardinal feature of acute myeloid leukemia (AML), however, exactly how mutations synergize to remodel the epigenetic landscape and rewire 3-Dimensional (3-D) DNA topology is unknown. Here we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML, Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. These analyses allow the identification of long-range cis-regulatory circuits, including a novel super-enhancer of the Hoxa locus, as well as larger and more detailed gene-regulatory networks, whose importance we demonstrate through perturbation of network members.

cancer biology↗