Biology subjects

Ling, V.

Publications and source records attributed to Ling, V..

3 recordsLinked to original sources

bioRxiv2026

Dnmt3a-mutant Leukemia Stem Cells evade chemotherapy through enforced quiescence in Npm1c-Flt3ITD Acute Myeloid Leukemia

Concurrent mutations in DNMT3A, NPM1, and FLT3 define a high-risk subtype of acute myeloid leukemia (AML) associated with increased relapse risk and inferior survival following standard chemotherapy. However, the mechanisms by which DNMT3A mutations promote treatment resistance in NPM1c-FLT3ITD AML remain unclear. Using genetically engineered murine models of Npm1c-Flt3ITD AML with or without Dnmt3aR878H (homologous to human DNMT3AR882H), we demonstrate that Dnmt3aR878H promotes chemotherapy resistance through epigenetic regulation of leukemia stem cell (LSC) quiescence. Integrated transcriptomic and epigenetic profiling revealed coordinated remodeling of DNA methylation and chromatin accessibility in LSC-enriched populations, characterized by preferential hypomethylation and increased accessibility at loci associated with stemness and quiescence programs. These data were confirmed in human DNMT3AR882H-NPM1c-FLT3ITD AML datasets with enrichment of quiescence-associated and stem cell enriched transcriptional programs. Conversely, Dnmt3a-mutant LSCs retained sensitivity to the cell-cycle independent regimen venetoclax plus azacitidine, but residual LSCs exhibited transcriptional plasticity and reversion to a de-differentiated state. We have identified LSC heterogeneity spanning primitive hematopoietic stem cell (HSC)-and progenitor-like states and our data demonstrate preferential maintenance of a quiescent HSC-like LSC subpopulation in Dnmt3aR878H-mutant AML following chemotherapy treatment. Pharmacologic induction of cell-cycle entry using pegylated interferon (pegIFN) disrupted the quiescent LSC state and restored chemotherapy sensitivity, identifying quiescence as a reversible and therapeutically actionable mechanism of resistance. These findings identify DNMT3A-mediated epigenetic regulation of LSC quiescence as a conserved mechanism of standard chemotherapy resistance and position therapeutic reactivation of quiescent LSCs as a promising strategy to overcome chemotherapy resistance and improve outcomes in high-risk DNMT3A-mutant AML.

cancer biology↗

bioRxiv2022

Magnetic torque-driven living microrobots for enhanced tumor infiltration

Bacterial microrobots combining self-propulsion and magnetic guidance are increasingly recognized as promising drug delivery vehicles for targeted cancer therapy. Thus far, control strategies have either relied on poorly scalable magnetic field gradients or employed directing magnetic fields with propulsive forces limited by the bacterial motor. Here, we present a magnetic torque-driven actuation scheme based on rotating magnetic fields to wirelessly control Magnetospirillum magneticum AMB-1 bearing versatile liposomal cargo. We observed a 4-fold increase in conjugate translocation across a model of the vascular endothelium and found that the primary mechanism driving this increased transport is torque-driven surface exploration at the cell interface. Using spheroids as a 3D tumor model, fluorescently labeled bacteria colonized their core regions with up to 21-fold higher signal in samples exposed to rotating magnetic fields. In addition to enhanced transport, we demonstrated the suitability of this magnetic stimulus for simultaneous actuation and inductive detection of AMB-1. Finally, we demonstrated that RMF significantly enhances AMB-1 tumor accumulation in vivo following systemic intravenous administration in mice. Our findings suggest that scalable magnetic torque-driven control strategies can be leveraged advantageously with biohybrid microrobots. One-Sentence SummaryMagnetic torque-driven motion enhances infiltration of living microrobots across physiological barriers both in vitro and in vivo.

bioengineering↗

bioRxiv2021

Three-dimensional in vitro model of the device-tissue interface reveals innate neuroinflammation can be mitigated by antioxidant ceria nanoparticles

The recording instability of neural implants due to neuroinflammation at the device-tissue interface (DTI) is a primary roadblock to broad adoption of brain-machine interfaces. While a multiphasic immune response, marked by glial scaring, oxidative stress (OS), and neurodegeneration, is well-characterized, the independent contributions of systemic and local "innate" immune responses are not well-understood. Three-dimensional primary neural cultures provide a unique environment for studying the drivers of neuroinflammation by decoupling the innate and systemic immune systems, while conserving an endogenous extracellular matrix and structural and functional network complexity. We created a three-dimensional in vitro model of the DTI by seeding primary cortical cells around microwires. Live imaging of microtissues over time revealed independent innate neuroinflammation, marked by increased OS, decreased neuronal density, and increased functional connectivity. We demonstrated the use of this model for therapeutic screening by directly applying drugs to neural tissue, bypassing low bioavailability through the in vivo blood brain barrier. As there is growing interest in long-acting antioxidant therapies, we tested efficacy of "perpetual" antioxidant ceria nanoparticles, which reduced OS, increased neuronal density, and protected functional connectivity. Overall, our avascular in vitro model of the DTI exhibited symptoms of OS-mediated innate neuroinflammation which were mitigated by antioxidant intervention.

bioengineering↗