A5060469663- Acute Myeloid Leukemia Research
- CRISPR and Genetic Engineering
- Hematopoietic Stem Cell Transplantation
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Multiple Myeloma Research and Treatments
- Virus-based gene therapy research
- Histone Deacetylase Inhibitors Research
- Cancer-related gene regulation
- T-cell and B-cell Immunology
- CAR-T cell therapy research
- Immune Cell Function and Interaction
- Ubiquitin and proteasome pathways
- SARS-CoV-2 and COVID-19 Research
- HIV Research and Treatment
- Cancer Genomics and Diagnostics
- Mesenchymal stem cell research
- RNA Interference and Gene Delivery
- Retinoids in leukemia and cellular processes
- Genomics and Chromatin Dynamics
- Immune responses and vaccinations
- Immune cells in cancer
- Cytomegalovirus and herpesvirus research
- Cancer-related molecular mechanisms research
- Nutrition, Genetics, and Disease
Institute for Research in Immunology and Cancer
2014-2024
Université de Montréal
2014-2024
University of British Columbia
2010-2017
Medical Genetics Center
2010
Research Institute of Molecular Pathology
2003
Highlights•Set7 binds Yap and promotes its cytoplasmic sequestration by the Hippo pathway•Methyltransferase activity of Set7 is required for proper localization•Yap monomethylated at lysine 494•Hippo signaling requires K494 to induce localizationSummaryMethylation nonhistone proteins emerging as a regulatory mechanism control protein function. (Setd7) SET-domain-containing methyltransferase that methylates alters function variety in vitro, but vivo relevance has not been established. We...
Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/EHMT2 a selective regulator of fast proliferating myeloid progenitors with no discernible function hematopoietic stem cells (HSCs). In mouse models acute leukemia (AML), loss G9a significantly delays disease progression reduces cell (LSC) frequency. We connect this its activity...
Accumulating evidence suggests that the regulation of gene expression by histone lysine methylation is crucial for several biological processes. The methyltransferase G9a responsible majority dimethylation H3 at 9 (H3K9me2) and required efficient repression developmentally regulated genes during embryonic stem cell differentiation. However, whether plays a similar role in adult cells still unclear. We identify critical CD4(+) T helper (Th) differentiation function. G9a-deficient Th are...
Methylation on lysine 9 of histone H3 (H3K9me) and DNA methylation play important roles in the transcriptional silencing specific genes repetitive elements. Both marks are detected class I II endogenous retroviruses (ERVs) murine embryonic stem cells (mESCs). Recently, we reported that H3K9-specific methyltransferase (KMTase) Eset/Setdb1/KMT1E is required for H3K9me3 maintenance ERVs mESCs. In contrast, G9a/Ehmt2/KMT1C dispensable, despite fact this KMTase H3K9 dimethylation (H3K9me2)...
Abstract Bone marrow haematopoietic stem cells (HSCs) are vital for lifelong maintenance of healthy haematopoiesis. In inbred mice housed in gnotobiotic facilities, the top hierarchy is occupied by dormant HSCs, which reversibly exit quiescence during stress. Whether HSC dormancy exists humans remains debatable. Here, using single-cell RNA sequencing, we show a continuous landscape highly purified human bone HSCs displaying varying degrees dormancy. We identify orphan receptor GPRC5C,...
Transplantation of expanded hematopoietic stem cells (HSCs) and gene therapy based on HSC engineering have emerged as promising approaches for the treatment hematological diseases. Nevertheless, immunophenotype cultured HSCs remains poorly defined. Here, we identify Integrin-α3 (ITGA3) a marker human HSCs. Exploiting pyrimidoindole derivative UM171 to expand cord blood (CB) cells, show that ITGA3 expression is sufficient separate primitive EPCR+CD90+CD133+CD34+CD45RA- population into two...
Purpose:RUNX1-mutated (RUNX1mut) acute myeloid leukemia (AML) is associated with adverse outcome, highlighting the urgent need for a better genetic characterization of this AML subgroup and design efficient therapeutic strategies disease. Toward goal, we further dissected mutational spectrum gene expression profile RUNX1mut correlated these results to drug sensitivity identify novel compounds targeting subgroup.Experimental Design: RNA-sequencing 47 primary specimens was performed sequencing...
Elucidation of the molecular cues required to balance adult stem cell self-renewal and differentiation is critical for advancing cellular therapies. Herein, we report that hematopoietic (HSC) agonist UM171 triggers a balanced pro- anti-inflammatory/detoxification network relies on NFKB activation protein C receptor-dependent ROS detoxification, respectively. We demonstrate within this network, EPCR serves as protective component its deletion hypersensitizes primitive cells pro-inflammatory...
Patients diagnosed with acute myeloid leukemia complex karyotype (CK AML) have an adverse prognosis using current therapies, especially when accompanied by TP53 alterations. We hereby report the RNA-sequencing analysis of 68 CK AML samples included in Leucegene 415 patient cohort. confirm frequent occurrence alterations this subgroup and further characterize allele expression profile transcript gene. also document that RAS pathway (N/KRAS, NF1, PTPN11, BRAF) is frequently altered disease....
Leukemia stem cells (LSCs) share numerous features with healthy hematopoietic (HSCs). G-protein coupled receptor family C group 5 member (GPRC5C) is a regulator of HSC dormancy. However, GPRC5C functionality in acute myeloid leukemia (AML) yet to be determined. Within patient AML cohorts, high levels correlated poorer survival. Ectopic Gprc5c expression increased aggression through the activation NF-κB, which resulted an altered metabolic state intracellular branched-chain amino acids...
Precision gene editing in primary hematopoietic stem and progenitor cells (HSPCs) would facilitate both curative treatments for monogenic disorders as well disease modelling. Precise efficiencies even with the CRISPR/Cas system, however, remain limited. Through an optimization of guide RNA delivery, donor design, additives, we have now obtained mean precise >90% on cord blood HSCPs minimal toxicity without observed off-target editing. The main protocol modifications needed to achieve such...
Here we investigate the role of epigenetic factors in controlling timing cranial neural crest cell differentiation. The gene coding for histone H3 lysine 9 methyltransferase G9A was conditionally deleted cells with Wnt1-Cre. majority homozygous-null animals survived to birth but thereafter failed thrive. Phenotypic analysis postnatal revealed that mutants displayed incomplete ossification and 20% shorter jaws as compared their wild-type littermates. At E13.5, patterns expression osteogenic...
High-mobility group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein that normally expressed in stem cells of various tissues and aberrantly detected several tumor types. We recently observed one-fourth human acute myeloid leukemia (AML) specimens express HMGA2, which associates with very poor prognosis. present results indicating HMGA2+ AMLs share distinct transcriptional signature representing an immature phenotype. Using single-cell analyses, we showed HMGA2 CD34+ subsets early...
The ubiquitin-associated protein 2–like (UBAP2L) gene remains poorly studied in human and mouse development. UBAP2L interacts with the Polycomb group B lymphoma Mo-MLV insertion region 1 homolog (BMI1) determines activity of hematopoietic stem cells vivo. Here we show that loss Ubap2l leads to disorganized respiratory epithelium mutant neonates, which die failure. We also overexpression epithelial-mesenchymal transition–like phenotype a non-small cell lung carcinoma (NSCLC) line. is...
Abstract Precision gene editing in primary hematopoietic stem and progenitor cells (HSPCs) would facilitate both curative treatments for monogenic disorders as well disease modelling. Precise efficiencies even with the CRISPR/Cas system, however, remain limited. Through an optimization of guide RNA delivery, donor design, additives, we have now obtained mean precise >90% on cord blood HSCPs minimal toxicity without observed off-target editing. The main protocol modifications needed to...
Precision gene editing in primary hematopoietic stem and progenitor cells (HSPCs) would facilitate both curative treatments for monogenic disorders as well disease modelling. Precise efficiencies even with the CRISPR/Cas system, however, remain limited. Through an optimization of guide RNA delivery, donor design, additives, we have now obtained mean precise >90% on cord blood HSCPs minimal toxicity without observed off-target editing. The main protocol modifications needed to achieve such...