Biology subjects

Matthews, M.

Publications and source records attributed to Matthews, M..

4 recordsLinked to original sources

bioRxiv2026

Biomarker-Targeted O6-Guanine Alkylation Potentiates ATR Inhibitor Response in De Novo and Relapsed/Refractory AML

Acute myeloid leukemia (AML) remains limited by high relapse rates and a scarcity of biomarker-directed therapies, underscoring the need to identify actionable vulnerabilities and mechanisms of therapeutic resistance. O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme that directly reverses mutagenic O6-alkylguanine lesions, is epigenetically silenced in multiple cancers. Although MGMT silencing is predictive of temozolomide (TMZ) response in glioblastoma with significant survival advantage, prior clinical trials of TMZ in AML have shown only modest responses. Therefore, the prevalence and therapeutic relevance of MGMT silencing, as well as genetic factors that modify its therapeutic response in AML, remain to be comprehensively investigated. Here, we first profiled MGMT status across a diverse cohort of 23 de novo and 16 relapsed/refractory (R/R) primary AMLs using an integrated analysis of MGMT mRNA expression, promoter methylation, and protein expression. We found that approximately 25-30% of AMLs harbor MGMT silencing, in contrast to consistent MGMT expression in healthy CD34+ hematopoietic stem and progenitor cells. We further identified frequent loss of mismatch repair (MMR) proteins in these AML cohorts, a known resistance mechanism against TMZ in glioblastoma. Using CRISPR knockout screening and genetically engineered AML models, we found that MMR loss also drives both upfront and acquired TMZ resistance in MGMT-silenced AML. These findings identify MMR deficiency as an important and previously underappreciated genetic contributor to the modest responses observed in prior trials of TMZ in AML. To therapeutically exploit MGMT silencing while bypassing genetic determinants of resistance, including MMR deficiency, we evaluated clinically and preclinically characterized MGMT-dependent DNA-alkylating agents and identified a fluoroethylating analog of TMZ, N3-(2-fluoroethyl) imidazotetrazine (KL50), with pronounced and selective activity in MGMT-silenced AML. KL50 retained antileukemic activity irrespective of MMR status, significantly prolonging survival in humanized MISTRG6 mice harboring primary AML patient-derived xenografts. Mechanistically, KL50 induced DNA damage through the time-dependent formation of interstrand DNA crosslinks, bypassing MMR dependence and triggering a replication stress response dominated by ATR signaling. Pharmacologic ATR inhibition synergized with KL50, producing marked antileukemic activity and significantly extending survival across AML models without compromising hematologic safety. Together, these findings establish MGMT silencing as a prevalent and therapeutically actionable biomarker in AML, define MMR status as a key determinant of TMZ response in AML but not KL50 sensitivity, and provide a translational rationale for combining low-dose O6-fluoroethylating imidazotetrazines with ATR inhibitors to target both de novo and R/R AML across diverse genetic backgrounds.

cancer biology↗

bioRxiv2023

Collateral sensitivity increases the efficacy of a rationally designed bacteriophage combination to control Salmonella enterica

The ability of virulent bacteriophages to lyse bacteria influences bacterial evolution, fitness, and population structure. Knowledge of both host susceptibility and resistance factors is crucial for the successful application of bacteriophages as biological control agents in clinical therapy, food processing and agriculture. In this study, we isolated twelve bacteriophages termed SPLA phage which infect the foodborne pathogen Salmonella enterica. To determine phage host range, a diverse collection of Enterobacteriaceae and Salmonella enterica were used and genes involved in infection by six SPLA phages were identified using Salmonella Typhimurium strain ST4/74. Candidate host receptors included lipopolysaccharide, cellulose and BtuB. Lipopolysaccharide was identified as susceptibility factor for phage SPLA1a and mutations in LPS biosynthesis genes spontaneously emerged during culture with S. Typhimurium. Conversely, LPS was a resistance factor for phage SPLA5b that suggested that emergence of LPS mutations in culture with SPLA1a may represent a case of collateral sensitivity to SPLA5b. We show that combination therapy with SPLA1a and SPLA5b was more successful in limiting the emergence of phage resistance compared to monotherapy. Identification of host susceptibility and resistance genes and understanding infection dynamics is critical step in rationale design of phage cocktails against specific bacterial pathogens.

microbiology↗

bioRxiv2022

Genetic architecture of spatially complex color patterning in hybrid Mimulus

Coloration in living organisms varies in hue, saturation, and pattern. Here we use genetic mapping to investigate all three elements in monkeyflowers Mimulus luteus var. variegatus and M. cupreus, whose flower petals differ in both yellow carotenoid and magenta anthocyanin pigmentation and whose hybrids exhibit anthocyanin pattern variation not seen in either parent. We report two QTLs associated with carotenoid intensity, and show that lighter yellow petals accumulate relatively high proportions of beta-carotene at the expense of downstream carotenoids. We propose that the derived loss of carotenoid saturation in M. l. variegatus is due to a function-reducing mutation in a Beta-Carotene Hydroxylase candidate gene, coupled with a reduction in the availability of carotenoid-storing chromoplasts influenced by the ORANGE candidate gene. We next identify five QTLs associated with the spatial patterning of anthocyanin pigment. Two QTLs, 9b and 23, each contain genes in the anthocyanin-activating subgroup of the MYB family. We hypothesize that MYB5a/NEGAN, at QTL-9b, activates spot formation in hybrids as part of a Turing-type reaction-diffusion system, while a MYB at QTL-23 activates solid, unpatterned anthocyanin pigment and may also be able to activate the variegatus allele of MYB5a/NEGAN. In addition to the apparently stochastic placement of most spots (consistent with a Turing mechanism), some pattern aspects - notably spots at the petal tips - appear to conform to a positional specification model in which spot location is predetermined. Collectively, this work begins to identify how combinations of yellow and red hues, shifts in carotenoid intensity, and two cryptic patterning systems all contribute to the complexity of color divergence between two close relatives.

genetics↗

bioRxiv2018

Hawkmoth flight in the unsteady wakes of flowers

Flying animals maneuver and hover through environments where wind gusts and flower wakes produce unsteady flow. Although both flight maneuvers and aerodynamic mechanisms have been studied independently, little is known about how these interact in an environment where flow is already unsteady. Moths forage from flowers by hovering in the flowers wake. We investigate hawkmoths tracking a 3D-printed robotic flower in a wind tunnel. We visualize the flow in the wake and around the wings and compare tracking performance to previous experiments in a still air flight chamber. Like in still air, moths flying in the flower wake exhibit near perfect tracking at low frequencies where natural flowers move. However, tracking in the flower wake results in a larger overshoot between 2-5 Hz. System identification of flower tracking reveals that moths also display reduced-order dynamics in wind, compared to still air. Smoke visualization of the flower wake shows that the dominant vortex shedding corresponds to the same frequency band as the increased overshoot. Despite these large effects on tracking dynamics in wind, the leading edge vortex (LEV) remains bound to the wing throughout the wingstroke and does not burst. The LEV also maintains the same qualitative structure seen in steady air. Persistence of a stable LEV during decreased flower tracking demonstrates the interplay between hovering and maneuvering.\n\nSummary statementWe examined how moths maneuver in the wake of flowers and discover that flower tracking dynamics are simplified compared to still air, while the leading edge vortex does not burst and extends continuously across the wings and thorax.

animal behavior and cognition↗