A5012030921- CAR-T cell therapy research
- Acute Myeloid Leukemia Research
- Chronic Myeloid Leukemia Treatments
- Immune Cell Function and Interaction
- Cancer-related gene regulation
- Chronic Lymphocytic Leukemia Research
- CRISPR and Genetic Engineering
- Acute Lymphoblastic Leukemia research
- RNA Interference and Gene Delivery
- Epigenetics and DNA Methylation
- Virus-based gene therapy research
- Advanced biosensing and bioanalysis techniques
- T-cell and B-cell Immunology
- Viral Infectious Diseases and Gene Expression in Insects
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Bone and Joint Diseases
- Biosimilars and Bioanalytical Methods
- Monoclonal and Polyclonal Antibodies Research
- Hemoglobinopathies and Related Disorders
- RNA regulation and disease
- Protein Degradation and Inhibitors
- Congenital heart defects research
- Genomics and Chromatin Dynamics
- Lysosomal Storage Disorders Research
- RNA Research and Splicing
Memorial Sloan Kettering Cancer Center
2020-2025
Kettering University
2022-2023
China National Petroleum Corporation (China)
2023
Boston Children's Hospital
2018-2019
Broad Institute
2019
Dana-Farber Cancer Institute
2019
Harvard University
2018
Harvard–MIT Division of Health Sciences and Technology
2018
Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through mechanisms, including acquired mutations in BTK at residue C481, binding site covalent inhibitors. Noncovalent (reversible) overcome this mechanism and other sources resistance, but mechanisms to these therapies are currently not well understood.
Increasing use of covalent and noncovalent inhibitors Bruton's tyrosine kinase (BTK) has elucidated a series acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance distinct enzymatic activities, including some that impair activity while imparting novel protein-protein interactions sustain receptor (BCR) signaling. Furthermore, describe clinical-stage IKZF1/3 degrader, NX-2127, can bind proteasomally degrade each mutant proteoform,...
Abstract The B/T subtype of mixed phenotype acute leukemia (B/T MPAL) is defined by co‐expression antigens both B‐ and T‐cell lineages on leukemic blasts. Although it has been suggested that multilineage antigen expression portends poor response to chemotherapy, the clinical characteristics driver mutations underlie pathogenesis this rare are scarcely known. We identified nine cases MPAL from multiple institutions correlated immunophenotypic findings with next‐generation sequencing data....
Mutations in RNA splicing factor genes are common patients with myelodysplastic neoplasms (MDS) and secondary acute myeloid leukemia (AML) [1][2][3].Cells bearing these mutations have been shown to be preferentially sensitive pharmacologic modulation of compared wild-type (WT) cells [4,5].Protein arginine methyltransferase 5 (PRMT5) is an which utilizes the methyl donor S-adenosylmethionine (SAM) symmetrically methylate residues on a variety proteins [6,7].PRMT5-dependent symmetric di-methyl...
Studies of allelic variation underlying genetic blood disorders have provided important insights into human hematopoiesis. Most often, the identified pathogenic mutations result in loss-of-function or missense changes. However, assessing pathogenicity noncoding variants can be challenging. Here, we characterize two unrelated patients with a distinct presentation dyserythropoietic anemia and other impairments hematopoiesis associated an intronic mutation GATA1 that is 24 nucleotides upstream...
Abstract Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success targeting surface antigens AML, part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping AML coupled with proteogenomics identified unique a variety antigens, including RNA helicase U5 snRNP200, on cells but not hematopoietic precursors skewed Fc receptor distribution immune microenvironment. Cell membrane localization snRNP200 was...
DNA methylation plays an essential role in mammalian genomes and expression of the responsible enzymes is tightly controlled. Deregulation de novo methyltransferase DNMT3B frequently observed across cancer types, yet little known about its ectopic genomic targets. Here, we used inducible transgenic mouse model to delineate rules for abnormal targeting, as well constraints activity different cell types. Our results explain preferential susceptibility certain CpG islands aberrant point...
An important way to improve the resolution of electromagnetic exploration is by using known seismic and logging data. Based on previous work, 2D magnetotelluric (MT) parallel-constrained-inversion, based an artificial-fish-swarm algorithm further developed. The finite-difference (FD) method with paralleling frequency used for MT-forward-modeling, computational efficiency. results FD finite-element (FE) methods show that accuracy comparable FE in case suitable mesh-generation; however,...
Chimeric antigen receptor (CAR) T-cell therapy has resulted in remarkable clinical success the treatment of B-cell malignancies. However, its efficacy solid tumors is limited, primarily by target heterogeneity. To overcome heterogeneity, we developed CAR T cells that overexpress LIGHT, a ligand both lymphotoxin-β on cancer and herpes virus entry mediator immune cells. LIGHT-expressing displayed antigen-directed cytotoxicity mediated antigen-independent killing through interaction LIGHT with...
<p>(A) ELISA quantification of soluble LIGHT in cell culture media after 24 hours incubation. (B) Supernatant from LIGHT-CAR T cells and second-generation CAR were added to corresponding vitro cytolysis was assessed against AsPC1. Data is representative 2 independent experiments two different donors. (C) MIAPACA2. (D) Cytotoxicity assay with various mesothelin-directed constructs the addition recombinant 3 (E) Mesothelin-directed exhibited similar proliferation a repetitive antigen...
<p>(A) Violin plots showing quality metrics of single cells included in downstream analysis. nCount RNA: number RNA unique molecular identifiers (UMI); nFeature detected genes; nCount_ADT: antibody UMI; nFeature_ADT: antibodies; percent.mt: percentage mitochondrial gene expression; HTO_margin: difference between signals for the hashtag with highest signal and second signal. (B) (C) Weighted-nearest neighbor (WNN) UMAP colored by condition (CAR T cell construct timepoint) (top) CD4+ vs...
<p>(A) Flow cytometric analysis of LTβR expression MIAPACA2 cells after CRISPR knockout (KO). KO were also transduced with non-signaling without intracellular signaling portion (tLTBR). (B) healthy human donor-derived mesothelin-targeted CAR T cocultured tumor expressing GFP and firefly luciferase at different effector to ratios. Bioluminescence was measured 72 hours later plotted as a percentage the signal detected in coculture non-functional Meso-DEL-CAR cells. Plots represent 3...
<p>(A) CAR T cells infiltration and expression of LIGHT at the tumor site was quantified by flow cytometric analysis on day 14 post cell treatment. (B) (C) Quantification per gram AsPC1 mass Plot is representative 4 to 5 mice treatment group. Immunohistochemistry staining mesothelin-negative cancer line, Panc1. Negative control. (D) mesothelin-positive MDA-MB-231. Positive (E) various PDX slides samples validate their mesothelin expression. (F) Flow in PDAC2, one selected for vivo...
<p>(A) Histopathological analysis images of certain organs in the 3 CAR-treated groups following full necropsy on day 30. Representative regions displaying lesion or absence at 20magnification are stained with H&E. Scale bar 100 microns. (B) Histologic examination various and tissues 30 after CAR T cell treatment. (C) Serum chemistry values mice Red represents higher than reference range blue lower range.</p>
<p>(A) Transgene expression of the CAR constructs after retroviral transduction human T cells by flow cytometry. CD19 were used as irrelevant cell control. (B-D) Healthy donor-derived mesothelin-targeted cocultured with tumor expressing GFP and firefly luciferase at different effector to ratios. Bioluminescence was measured 72 hours later plotted a percentage signal detected alone (max bioluminescence signal). Associated mesothelin corresponding mesothelin-positive lines are shown. JMN...
<div>Abstract<p>Chimeric antigen receptor (CAR) T-cell therapy has resulted in remarkable clinical success the treatment of B-cell malignancies. However, its efficacy solid tumors is limited, primarily by target heterogeneity. To overcome heterogeneity, we developed CAR T cells that overexpress LIGHT, a ligand both lymphotoxin-β on cancer and herpes virus entry mediator immune cells. LIGHT-expressing displayed antigen-directed cytotoxicity mediated antigen-independent killing...