A5028361543- Acute Myeloid Leukemia Research
- Epigenetics and DNA Methylation
- Immune cells in cancer
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- Cancer Genomics and Diagnostics
- Ubiquitin and proteasome pathways
- Vascular Tumors and Angiosarcomas
- T-cell and B-cell Immunology
- Sulfur Compounds in Biology
- Glutathione Transferases and Polymorphisms
- Redox biology and oxidative stress
- Single-cell and spatial transcriptomics
- Cancer-related Molecular Pathways
- DNA Repair Mechanisms
- Hemoglobinopathies and Related Disorders
- Phagocytosis and Immune Regulation
- PI3K/AKT/mTOR signaling in cancer
- Autophagy in Disease and Therapy
- CNS Lymphoma Diagnosis and Treatment
- Cell death mechanisms and regulation
- Cancer, Hypoxia, and Metabolism
- Acute Lymphoblastic Leukemia research
- Sarcoma Diagnosis and Treatment
- Retinoids in leukemia and cellular processes
Hong Kong Science and Technology Parks Corporation
2023-2024
University Health Network
2012-2023
Princess Margaret Cancer Centre
2016-2023
Ontario Institute for Cancer Research
2008-2016
Resident macrophages orchestrate homeostatic, inflammatory, and reparative activities. It is appreciated that different tissues instruct specialized macrophage functions. However, individual contain heterogeneous subpopulations, how these subpopulations are related unclear. We asked whether common transcriptional functional elements could reveal an underlying framework across tissues. Using single-cell RNA sequencing random forest modeling, we observed four genes predict three subsets were...
Tumorigenesis results from dysregulation of oncogenes and tumor suppressors that influence cellular proliferation, differentiation, apoptosis, and/or senescence. Many gene products involved in these processes are substrates the E3 ubiquitin ligase Mule/Huwe1/Arf-BP1 (Mule), but whether Mule acts as an oncogene or suppressor vivo remains controversial. We generated K14Cre;Mule flox/flox(y) (Mule kKO) mice subjected them to DMBA/PMA-induced skin carcinogenesis, which depends on oncogenic Ras...
Mutations in the tumor suppressor BRCA1 predispose women to breast and ovarian cancers. The mechanism underlying tissue-specific nature of BRCA1's suppression is obscure. We previously showed that antioxidant pathway regulated by transcription factor NRF2 defective BRCA1-deficient cells. Reactivation through silencing its negative regulator KEAP1 permitted survival BRCA1-null Here we show estrogen (E2) increases expression NRF2-dependent genes various E2-responsive cell types. Like...
Significance Current genomic and biochemical analysis revealed mutations in isocitrate dehydrogenase ( IDH ) genes associated with several neoplasms a novel enzymatic activity of to catalyze α-ketoglutarate d -2-hydroxyglutarate, contributing tumorigenesis. We identified broad range IDH1 mutations, including previously unidentified -R132Q mutation, cartilage tumors. Cartilage-specific Col2a1-Cre/ERT2;Idh1-R132 mutant knock-in mice developed multiple enchondroma-like lesions. These data show...
Significance Mutations in isocitrate dehydrogenase ( IDH ) 1 and IDH2 contribute to malignant progression by producing the oncometabolite 2HG. In myeloid disorders, mutations at three positions these genes are commonly observed, but angioimmunoblastic T-cell lymphoma (AITL), restricted arginine (R) 172. The complex microenvironment of AITL, where T cells comprise a minority tumor, has made it difficult evaluate role this mutation. Here, we provide clinical data showing that mutant expression...
Significance Defects in spermatogenesis, many of which are unexplained, underlie the infertility problems ∼20% couples. Although specific roles for p53 family members female fertility have been described, their involvement spermatogenesis is largely unexpected. Using gene-targeted mice, we demonstrated that deficiency TAp73, but not or ∆Np73, leads to male caused by severely impaired germ cell differentiation and maturation viable sperms testes. Importantly, our work has established p53,...
Cellular homeostasis is controlled by pathways that balance cell death with survival. Mcl-1 ubiquitin ligase E3 (Mule) an targets the proapoptotic molecule p53 for polyubiquitination and degradation. To elucidate role of Mule in B lymphocyte homeostasis, cell–specific knockout (BMKO) mice were generated using Cre–LoxP recombination system. Analysis BMKO showed was essential development, proliferation, humoral immune responses. transactivation increased two- to fourfold Mule-deficient cells...
A hallmark of cancer, including pancreatic ductal adenocarcinoma (PDA), is a massive stromal and inflammatory reaction. Many efforts have been made to identify the anti- or protumoral role cytokines immune subpopulations within stroma. Here, we investigated interleukin-17A (IL17A) its effect on tumor fibroblasts microenvironment. We used spontaneous PDA mouse model (KPC) crossed IL17A knockout mice show an extensive desmoplastic reaction, without impaired infiltration. Macrophages,...
Mutations in IDH1,IDH2, and TET2 are recurrently observed myeloid neoplasms. IDH1 IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading production D-2-hydroxyglutarate (D-2-HG), a potent inhibitor α-KG-dependent enzymes include TET methylcytosine dioxygenases. Given their mutual exclusivity neoplasms, IDH1, IDH2, may converge on common oncogenic mechanism. Contrary...
TNF receptor-associated factor 2 (TRAF2) is a key intracellular signaling mediator that acts downstream of not only TNFα but also various members the superfamily. Here, we report that, despite their lack signaling, TRAF2(-/-)TNFα(-/-) mice develop an inflammatory disorder characterized by autoantibody accumulation and organ infiltration T cells with phenotypes activated, effector, memory cells. RAG1(-/-) reconstituted bone marrow showed increased numbers hyperactive rapidly developed...
Abstract T-cell proliferation is regulated by ubiquitination but the underlying molecular mechanism remains obscure. Here we report that Lys-48-linked of transcription factor KLF4 mediated E3 ligase Mule promotes entry into S phase. elevated in T cells upon TCR engagement, and deficiency blocks because accumulates drives upregulation its transcriptional targets E2F2 cyclin-dependent kinase inhibitors p21 p27. T-cell-specific knockout (TMKO) mice develop exacerbated experimental autoimmune...
Although the enzymatic activity of isocitrate dehydrogenase 1 (IDH1) was defined decades ago, its functions in vivo are not yet fully understood. Cytosolic IDH1 converts to α-ketoglutarate (α-KG), a key metabolite regulating nitrogen homeostasis catabolic pathways. It thought that might enhance lipid biosynthesis liver or adipose tissue by generating NADPH, but we show here contents relatively unchanged both IDH1-null mouse and IDH1-deficient HepG2 cells generated using CRISPR-Cas9 system....
Significance T-cell homeostasis is a tightly regulated process that ensures constant number of naïve T cells in the periphery an organism. Mechanisms promote survival and homeostatic proliferation peripheral are essential for maintaining this balance thus effective immunity against pathogens incipient tumors. We have identified UV radiation resistance-associated gene (UVRAG), autophagic tumor suppressor many cell lineages, as novel nonautophagic regulator homeostasis. Furthermore, our...
Significance Isocitrate dehydrogenase 1 ( IDH1 ) mutations are drivers of hematological malignancy. Although these most often associated with myeloid disease, they also found in lymphoid malignancies, including T-cell acute lymphoblastic leukemia (T-ALL). Treatment strategies targeting currently being devised, small-molecule inhibitors the mutant enzyme. A better understanding role tumorigenesis and their effects on tumor cells will allow treatment to be effectively translated clinic. Here...
Abstract Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within microenvironment (TME) is unclear. We demonstrate that Fcmr (Toso), putative receptor for soluble IgM, modulates myeloid cell responses cancer. In a syngeneic melanoma model, ablation in suppressed growth and extended mouse survival. deficiency increased population density this malignancy enhanced anti-tumor immunity. Single-cell RNA sequencing...
Abstract PirB is an inhibitory cell surface receptor particularly prominent on myeloid cells. curtails the phenotypes of activated macrophages during inflammation or tumorigenesis, but its functions in macrophage homeostasis are obscure. To elucidate PirB-related at steady-state, we generated and compared single-cell RNA-sequencing (scRNAseq) datasets obtained from subsets wild type (WT) PirB-deficient knockout (PirB KO) mice. facilitate this analysis, developed a novel approach to...
In order to sustain proficient life-long hematopoiesis, hematopoietic stem cells (HSCs) must possess robust mechanisms preserve their quiescence and genome integrity. DNA-damaging stress can perturb HSC homeostasis by affecting survival, self-renewal, differentiation. Ablation of the kinase ataxia telangiectasia mutated (ATM), a master regulator DNA damage response, impairs fitness. Paradoxically, we show here that loss single allele Atm enhances functionality in mice. To explain this...
Abstract Mutations in IDH1, IDH2, and TET2 are recurrently observed myeloid neoplasms. IDH1 IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading production D-2-hydroxyglutarate (D-2-HG), a potent inhibitor α-KG-dependent enzymes include TET methylcytosine dioxygenases. Given their mutual exclusivity neoplasms, may converge on common oncogenic mechanism. Contrary this...