A5047996805- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Chronic Lymphocytic Leukemia Research
- Peptidase Inhibition and Analysis
- Acute Myeloid Leukemia Research
- Ubiquitin and proteasome pathways
- PARP inhibition in cancer therapy
- Lymphoma Diagnosis and Treatment
- CAR-T cell therapy research
- HIV/AIDS drug development and treatment
- Advanced biosensing and bioanalysis techniques
- Cancer-related gene regulation
- Sirtuins and Resveratrol in Medicine
- Immunodeficiency and Autoimmune Disorders
- CRISPR and Genetic Engineering
- Immune Cell Function and Interaction
- Phagocytosis and Immune Regulation
- RNA Interference and Gene Delivery
- Biochemical and Molecular Research
- HIV-related health complications and treatments
- Acute Lymphoblastic Leukemia research
- Autophagy in Disease and Therapy
- PI3K/AKT/mTOR signaling in cancer
- Advanced Breast Cancer Therapies
- T-cell and B-cell Immunology
The Ohio State University
2016-2023
Huntsman Cancer Institute
2020
University of Utah
2020
Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved pathogenesis chronic lymphocytic leukemia (CLL). is overexpressed CLL enriched proximal genes upregulated or de novo expressed with known functions disease progression. These genes, including members the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach new targets alternative...
Abstract DNA origami (DO) nanotechnology enables the construction of precise nanostructures capable functionalization with small molecule drugs, nucleic acids, and proteins, suggesting a promising platform for biomedical applications. Despite potential drug vaccine delivery, impact DO vehicles on immunogenicity in vivo is not well understood. Here, two vehicles, flat triangle nanorod, at varying concentrations are evaluated vitro repeated dosing regimen administered high dose to study early...
Abstract Acute myeloid leukemia (AML) is a heterogeneous and complex disease, treatments for this disease have not been curative the majority of patients. In younger patients, internal tandem duplication FLT3 ( -ITD) common mutation which two inhibitors (midostaurin gilteritinib) with varied potency specificity are clinically approved. However, high rate relapse or failed initial response AML patients suggests that addition second targeted therapy may be necessary to improve efficacy. Using...
Abstract Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ a potential therapeutic target AML. We evaluated effect KPT-9274, p21-activated kinase 4/NAMPT inhibitor that possesses unique NAMPT-binding profile based on silico modeling compared earlier compounds pursued against this target. KPT-9274 elicited loss mitochondrial respiration...
Abstract Background Exportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization critical regulators. However, pathogenic role played by change-in-function CLL not fully...
Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors and BCL2 antagonists. When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein composed of cyclin dependent 9 (CDK9) T1, functions to regulate short half-life transcripts by phosphorylation RNA Polymerase II (POLII). These frequently dysregulated in hematologic malignancies;...
Abstract Richter’s Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) implicated in lymphomagenesis, but its role CLL or RT unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 patients with to RT. Furthermore, mice B-specific overexpression hPRMT5 develop B-lymphoid expansion increased risk death, Eµ-PRMT5/TCL1 double...
Dysregulated cellular differentiation is a hallmark of acute leukemogenesis. Phosphatases are widely suppressed in cancers but have not been traditionally associated with differentiation. In this study, we found that the silencing protein phosphatase 2A (PP2A) directly blocks myeloid leukemia (AML). Gene expression and mass cytometric profiling revealed PP2A activation modulates cell cycle transcriptional regulators program terminal Using novel pharmacological agent, OSU-2S, parallel genetic...
Abstract Purpose: Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (NAMPTi) are currently in development, but may be limited as single-agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPTis required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen identify rational disease-specific partners novel NAMPTi, KPT-9274. Experimental...
The clinical benefit of CTLA-4 blockade on T cells is known, yet the impact its expression cancer remains unaddressed. We define an immunosuppressive role for tumor-expressed using chronic lymphocytic leukemia (CLL) as a disease model. CLL cells, among other are CTLA-4+ Coculture with activated human induced surface primary B cells. CLL-derived cell lines decreased CD80 cocultured CD80+ restoration upon blockade. CD80-GFP+ revealed transfer CD80-GFP into tumor similar to able...
Using a genome-wide CRISPR screen, we identified CDK9 , DHODH and PRMT5 as synthetic lethal partners with gilteritinib treatment in fms-like tyrosine kinase 3 ( FLT3 )–internal tandem duplication (ITD) acute myeloid leukemia (AML) genetically pharmacologically validated their roles sensitivity. The presence of -ITD is associated an increase anaerobic glycolysis, rendering cells highly sensitive to inhibition glycolysis. Supportive this, our data show the enrichment single guide RNAs...
Abstract Rare, recurrent balanced translocations occur in a variety of cancers but are often not functionally interrogated. Balanced with the immunoglobulin heavy chain locus ( IGH ; 14q32) chronic lymphocytic leukemia (CLL) infrequent have led to discovery pathogenic genes including CCND1 , BCL2 and BCL3 . Following identification t(X;14)(q28;q32) translocation that placed mature T cell proliferation 1 gene MTCP1 ) adjacent CLL patient, we hypothesized this may previously unrecognized...
Abstract Acute myeloid leukemia (AML) is the most prevalent adult characterized by genetic or mutational disruption of differentiation, growth arrest, and apoptosis. Standard “7 + 3” chemotherapy consisting cytarabine in combination with an anthracycline such as daunorubicin has been used for more than four decades. However this course only results 10 year disease free survival 15% patients age <60 years 2% among those > 60 years. Several new successful therapies AML are shown...
Abstract Chronic lymphocytic leukemia (CLL) is the most prevalent adult in Western countries and spelled by substantial genetic clinical heterogeneity. During CLL transformation, loss or gain of material appears to be a key determinant disease phenotype outcome, with major chromosome aberrations observed up 80% patients. Alternatively, balanced translocations, specifically those resulting constitutive over-expression various proto-oncogenes under immunoglobulin heavy chain locus (IGH;...
<p>Supplementary Methods</p>
<p>HDAC8-specific inhibitor (PCI-34051) or AR-42 treatments sensitize AML cell lines to KPT-9274 treatment.</p>
<p>Mutant IDH1/2 enhances AR-42/KPT-9274 combination sensitivity in a 2-HG-dependent manner.</p>
<p>Combined treatment of AR-42 and KPT-9274 leads to mitochondrial potential collapses in cell lines.</p>
<p>Knockdown of selected genes has modest effects on MOLM13 responses to KPT-9274 treatment.</p>