Biology subjects

Posey, R. R.

Publications and source records attributed to Posey, R. R..

4 recordsLinked to original sources

bioRxiv2026

Tumor suppressor-like mutations mark a dosage-constrained dependency in leukemia

Cancer genes are classically categorized as oncogenes or tumor suppressors based on whether gain or loss of function promotes malignancy. Here we show that oncogene-imposed dosage constraints can produce mutations that mimic tumor suppressor loss yet mark essential genes. In acute promyelocytic leukemia (APL), the transcription factor EBF3 gene harbors recurrent heterozygous loss-of-function mutations, a tumor suppressor signature, and is essential for APL survival. We resolve this paradox by showing that while PML::RARA, the fusion oncoprotein defining APL, drives EBF3 expression, excess EBF3 suppresses proliferation. Patient mutations reduce EBF3 activity through heterozygous inactivation, optimizing its expression within a corridor bounded by fitness constraints at both extremes. PML::RARA activates EBF3 via a p300-dependent intronic enhancer, and p300 inhibition exploits this constraint by suppressing EBF3 below the viability threshold. Our findings reveal that oncogenes can impose dosage constraints that drive adaptive mutations conventionally misclassified as tumor suppressor loss, with implications for interpreting cancer genomes.

cancer biology↗

bioRxiv2025

Endothelial CLK2 as a therapeutic target for acute radiation syndrome

Damage to the vascular endothelium is a major contributor to acute radiation injury in multiple organs that underlies acute radiation syndrome (ARS), yet there are no FDA-approved radiation countermeasures targeting endothelial cells. Use of kinome-scale CRISPR screens performed in cultured human vascular endothelial cells isolated from different organs identified CLK2 as a potential radioprotective target. Pharmacological inhibition of CLK2 using TG003 and Cirtuvivint protected these endothelial cells against radiation injury and reversed its effects across the transcriptome and phospho-proteome. Human Organ Chip models of human intestine and lung that contain organ-specific epithelium and microvascular endothelium faithfully replicated clinical features of ARS when exposed to radiation, which were prevented when treated with CLK2 inhibitors. Thus, CLK2 inhibitors may represent a new class of radiation countermeasure drugs that can protect multiple organs against radiation-induced toxicities in patients with ARS.

molecular biology↗

bioRxiv2023

Differences in syncytia formation by SARS-CoV-2 variants modify host chromatin accessibility and cellular senescence via TP53

COVID-19 remains a significant public health threat due to the ability of SARS-CoV-2 variants to evade the immune system and cause breakthrough infections. Although pathogenic coronaviruses such as SARS-CoV-2 and MERS-CoV lead to severe respiratory infections, how these viruses affect the chromatin proteomic composition upon infection remains largely uncharacterized. Here we used our recently developed integrative DNA And Protein Tagging (iDAPT) methodology to identify changes in host chromatin accessibility states and chromatin proteomic composition upon infection with pathogenic coronaviruses. SARS-CoV-2 infection induces TP53 stabilization on chromatin, which contributes to its host cytopathic effect. We mapped this TP53 stabilization to the SARS-CoV-2 spike and its propensity to form syncytia, a consequence of cell-cell fusion. Differences in SARS-CoV-2 spike variant-induced syncytia formation modify chromatin accessibility, cellular senescence, and inflammatory cytokine release via TP53. Our findings suggest that differences in syncytia formation alter senescence-associated inflammation, which varies among SARS-CoV-2 variants.

microbiology↗

bioRxiv2020

Hematopoietic p53 loss cell-extrinsically defines an immune infiltrated microenvironment in leukemia and pre-leukemia

TP53 is the most frequently mutated gene in human cancers. In Acute Myeloid Leukemia (AML) and Clonal Hematopoiesis of Indeterminate Potential (CHIP), it is one of several recurrent genetic alterations. Despite multiple recent therapeutic advances for AML, TP53 mutated AML is associated with resistance to currently approved therapies and thus, a very poor prognosis. Emerging evidence suggests that mutations in TP53 may be a predictor of positive response to immunotherapy. To model cell - extrinsic consequences of hematopoietic p53 loss, we generated bone marrow chimeric mice bearing p53-/- and congenic wild type cells. Following reconstitution, we observed increased levels of wild type CD8+ and CD4+ T cells in mice transplanted with p53-/- hematopoietic cells compared to controls. In addition, we observed a change in the frequency of T cell subsets in p53-/- chimeras including an increase in Tregs. To determine if these alterations were mirrored in the leukemic setting, we next generated p53-/-;nRasG12D leukemia. While the bone marrow of p53-/-;nRasG12D leukemia showed the presence of both T and B lymphocytes, MLL-AF9 showed a near complete absence of lymphocytes, akin to immune-infiltrated and immune-desert phenotypes seen in solid tumors. These data clearly demonstrate a causal cell-extrinsic effect of hematopoietic p53 loss on the immune system, both in the context of leukemia and preleukemic states. Modeling AML genetics in murine models serves as a powerful tool to define the association between genetic drivers and immune subtypes of AML towards precise patient stratification critical for the application of emerging targeted and immune therapies. Statement of SignificanceTP53 mutations are frequent in both AML and CHIP, and are associated with both resistance to therapy as well as very poor prognosis. We provide evidence to investigate the immunotherapy as a treatment option for this subgroup of AML.

cancer biology↗