Biology subjects

Stevens, A. M.

Publications and source records attributed to Stevens, A. M..

4 recordsLinked to original sources

bioRxiv2026

Disrupting a Convergent Acetylation Circuit Collapses Leukemic Identity Across AML Subtypes

Transcriptional condensates anchored by chromatin readers are increasingly recognized as organizing hubs for gene expression, but how their assembly and stability are regulated remains poorly understood. Here, we identify an acetylation-dependent feed-forward circuit that controls the integrity of the Super Elongation Complex (SEC), a key driver of transcriptional elongation. We show that the SAGA histone acetyltransferase catalytic subunits KAT2A/KAT2B license acetylation of both histone H3 lysine 9 (H3K9ac) and SEC components themselves, including ENL, AFF1, and AFF3. Loss of this dual acetylation activity, achieved via a cereblon-recruiting PROTAC (GSK983/GSK699), displaces the chromatin reader ENL from target loci, dissolves ENL-anchored transcriptional condensates, and disrupts SEC-dependent transcriptional output - linking histone and non-histone acetylation to the physical integrity of a core transcriptional machine. Using genome-scale dependency data, we show that the SAGA complex is a selective chromatin dependency in acute myeloid leukemia (AML) AML and hematological malignancies and disrupting this feed-forward transcriptional circuit in AML demonstrates subtype independent antileukemia effects. KAT2A/B degradation drives potent, broad-spectrum antileukemic activity across genetically diverse AML cell lines, primary patient samples, and an isogenic KMT2A-rearranged model bearing cooperating oncogenic mutations, with H3K9ac loss concentrated asymmetrically at core AML oncogene loci such as MYC, MYB, and the HOXA cluster. Together, these findings define an acetylation-dependent circuit governing SEC integrity and establish KAT2A/B degradation as a mechanism-based, pan-AML therapeutic strategy, with implications for transcriptional condensate regulation beyond leukemia. HIGHLIGHTSO_LIThe SAGA complex is a selectively essential chromatin dependency across hematological malignancies and particularly in AML C_LIO_LIKAT2A/B degradation drives broad anti-leukemic activity across genetically diverse AML subtypes including chemo-refractory disease C_LIO_LIKAT2A/B degradation depletes H3K9ac at AML oncogene loci and dismantles ENL-anchored condensates C_LIO_LIKAT2A/B licenses regulation of super elongation complex acetylation and ENL interaction with SEC complex components C_LI

cancer biology↗

bioRxiv2025

Characterization of Chemoresistant Cell Populations Improves Risk Stratification and Therapy Prediction in Pediatric AML

Most pediatric acute myeloid leukemia (pAML) patients achieve complete remission after chemotherapy, yet relapse is common, with nearly 40% ultimately dying of the disease. Prognosis is currently assessed using cytogenetic biomarkers and measurable residual disease after the first chemotherapy cycle, with the highest risk patients referred for stem cell transplantation (SCT) at first remission. Because aggressive therapies such as SCT are highly toxic, yet cures after relapse are rare, accurate early risk prediction is essential for improving outcomes. To address this need, we analyzed paired diagnosis-relapse samples from 33 pAML patients at single-cell resolution and identified chemoresistant cell populations whose abundance at diagnosis significantly improved risk prediction. Incorporating the detection of these cell populations into our risk model revealed a previously unrecognized patient subgroup with a 5-year event-free survival rate below 40%. Although this subgroup represents only 20% of pAML cases, it accounted for half of the deaths among patients who do not receive SCT at first remission. Moreover, molecular characterization of these chemoresistant cell populations uncovered potential therapeutic targets and candidate interventions relevant to most high-risk patients, paving the way for more effective targeted treatments for high-risk pAML patients.

cancer biology↗

bioRxiv2025

Dual Targeting of IKKβ and NR4A1 for AML Therapy

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor clinical outcomes and limited therapeutic options. Aberrant activation of the IKK{beta}-NF-{kappa}B pathway occurs in approximately 40% of AML cases and contributes to leukemogenesis. However, pharmacological inhibition of IKK{beta} has been limited by serious toxicities, including neutrophilia. Here we identify IKK{beta} and NR4A1 as critical drivers of AML progression in certain models and develop a proteolysis-targeting chimera (PROTAC) capable of degrading the proteins. Although NR4A1 has previously been described as a tumor suppressor in AML, our findings demonstrate that NR4A1 exhibits oncogenic functions in some AMLs of the (pro)monocytic lineage. Notably, elevated expression of IKK{beta} and NR4A1 in AML is associated with poor clinical outcomes, playing non-redundant oncogenic roles in AML. To therapeutically target IKK{beta} and NR4A1, we designed and synthesized a series of celastrol-based PROTACs that exploit celastrols ability to bind both IKK{beta} and NR4A1. Among these compounds, the lead A9 induces potent cytotoxicity in multiple AML cell lines and primary AML samples through cereblon E3 ligase-dependent degradation of IKK{beta} and/or NR4A1. In vivo, A9 suppresses leukemia progression in a KMT2A::MLLT3 AML mouse model without inducing neutrophilia, supporting PROTAC-mediated degradation of IKK{beta} and NR4A1 as a promising therapeutic strategy. Plain language summaryAcute myeloid leukemia (AML) is a predominant form of blood cancer with devastating consequences in both young and adult populations. Despite some advances in AML treatment over the last decade, there is still an unmet medical need to develop new drugs for difficult-to- treat AMLs. We discover that two proteins, namely IKK{beta} and NR4A1, play important roles in promoting the AML disease and could be associated with more severe AML subtypes. To target and destroy those proteins within AML cells, we employ a novel targeted protein degradation approach, which involved design, synthesis, and screening of PROTAC drugs, to discover a drug possessing pronounced AML cell killing activity by virtue of IKK{beta} and NR4A1 degradations. The drug also significantly reduces AML progression in mice without any noticeable adverse effects. Our current efforts involve more comprehensively testing the benefit of the drug (and its analogs) in a wide range of clinically relevant AML models. Key PointsO_LIIKK{beta} and NR4A1 are clinically relevant drivers of AML pathogenesis. C_LIO_LIA novel celastrol-based PROTAC can effectively degrade IKK{beta} and/or NR4A1 to potentially treat AML. C_LI

cancer biology↗

bioRxiv2018

Expanded Analysis of the Pantoea stewartii subsp. stewartii DC283 Complete Genome Reveals Plasmid-borne Virulence Factors

Pantoea stewartii subsp. stewartii, a Gram-negative proteobacterium, causes Stewarts wilt disease in corn. Bacterial transmission to plants occurs primarily via the corn flea beetle insect vector, which is native to North America. P. stewartii DC283 is the wild-type reference strain most used to study pathogenesis. Previously the complete genome of P. stewartii was released. Here, the method whereby the genome was assembled is described in greater detail. Data from a matepair library preparation with 3.5 kilobase insert size and high-throughput sequencing from the MiSeq Illumina platform, together with the available incomplete genome sequence of AHIE00000000.1 (containing 65 contigs) was used. This work resulted in the complete assembly of one circular chromosome, ten circular plasmids and one linear phage from P. stewartii DC283. A high number of sequences encoding repetitive transposases (> 400) were found in the complete genome. The separation of plasmids from genomic DNA revealed that two Type III secretion systems in P. stewartii DC283 are located on two separate mega-plasmids. Interestingly, the assembly identified a previously unknown 66-kb region in a location interior to a contig in the previous reference genome. Overall, a novel approach was successfully utilized to fully assemble a prokaryotic genome that contains large numbers of repetitive sequences and multiple plasmids, which resulted in some interesting biological findings.

bioinformatics↗