A5062138798- Acute Myeloid Leukemia Research
- Acute Lymphoblastic Leukemia research
- Hematopoietic Stem Cell Transplantation
- Immune cells in cancer
- Phagocytosis and Immune Regulation
- Sphingolipid Metabolism and Signaling
- Epigenetics and DNA Methylation
- Cancer Genomics and Diagnostics
- CRISPR and Genetic Engineering
- Immune Cell Function and Interaction
- RNA Interference and Gene Delivery
- Virus-based gene therapy research
- Single-cell and spatial transcriptomics
- MicroRNA in disease regulation
- Prenatal Screening and Diagnostics
- Cytokine Signaling Pathways and Interactions
- Cytomegalovirus and herpesvirus research
- CAR-T cell therapy research
- Calcium signaling and nucleotide metabolism
- Pluripotent Stem Cells Research
- RNA modifications and cancer
- Psoriasis: Treatment and Pathogenesis
- Endoplasmic Reticulum Stress and Disease
- Immune responses and vaccinations
- Wnt/β-catenin signaling in development and cancer
Icahn School of Medicine at Mount Sinai
2022-2025
Princess Margaret Cancer Centre
2018-2024
University Health Network
2018-2024
Mount Sinai Hospital
2023-2024
Mount Sinai Hospital
2024
Child Health and Development Institute
2023-2024
Stem Cell Institute
2024
Cancer Institute (WIA)
2024
Health Net
2022
University of Toronto
2019-2021
Highlights•ISR pathway activity in human HSC/MPPs is maintained by low eIF2 and high ATF4•ATF4 upregulation following amino acid deprivation promotes HSC survival•Functional HSCs can be purified using an ATF4 reporter that measures ISR activity•ISR marks primitive cells normal malignant hematopoietic hierarchiesSummaryLifelong maintenance of the blood system requires equilibrium between clearance damaged stem (HSCs) long-term survival pool. Severe perturbations cellular homeostasis result...
It is critical to understand how human quiescent long-term hematopoietic stem cells (LT-HSCs) sense demand from daily and stress-mediated cues then transition into bioenergetically active progeny differentiate meet these cellular needs. However, the demand-adapted regulatory circuits of early steps hematopoiesis are largely unknown. Here we show that lysosomes, sophisticated nutrient-sensing signaling centers, regulated dichotomously by transcription factor EB (TFEB) MYC balance catabolic...
Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism predisposition is unclear. Because leukemogenesis initiates during fetal development, we characterized cellular and developmental context preleukemic initiation leukemic progression using gene editing in human disomic trisomic hematopoietic cells xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term stem...
Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS occur invariably late in course of acute myeloid leukaemia, upon progression or relapsed/refractory disease1–6. Here, by using human leukaemogenesis models, we first that are obligatory events need to succeed earlier cooperating mutations. We provide mechanistic explanation this a requirement mutant specifically transform committed progenitors...
Abstract Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis driven from stem cells (LSC) that share some hematopoietic cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature and influences stemness lineage determination in HSCs by activating stress myelopoiesis, such roles LSCs are poorly understood. Here, we show S1PR3, receptor for the bioactive lipid sphingosine-1-phosphate, central regulator drives...
T-lineage acute lymphoblastic leukemia (ALL) is an aggressive cancer comprising diverse subtypes that are challenging to stratify using conventional immunophenotyping. To gain insights into subset-specific therapeutic vulnerabilities, we performed integrative multiomics analysis of bone marrow samples from newly diagnosed T cell ALL, early precursor and T/myeloid mixed phenotype leukemia. Leveraging cellular indexing transcriptomes epitopes in conjunction with receptor sequencing, identified...
Accumulating evidence links pediatric cancers to prenatal transformation events, yet the influence of developmental stage on oncogenesis remains elusive. We investigated how hematopoietic stem cell stages affect leukemic transformation, disease progression, and therapy response using a novel, humanized model NUP98::NSD1-driven acute myeloid leukemia, that is particularly aggressive with WT1 co-mutations. Fetal-derived cells readily transform into mutations further enhance stemness alter...
Abstract Inflammation activates many blood cell types, driving aging and malignancy. Yet, hematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long production. To understand HSC adaptation inflammation, we developed xenograft inflammation-recovery models performed single multiomics on isolated human HSC. Two transcriptionally epigenetically distinct subsets expressing canonical programs were identified. Only one showed sustained transcriptional epigenetic changes...
Abstract In the human hematopoietic system, rare self-renewing multipotent long-term stem cells (LT-HSCs) are responsible for lifelong production of mature blood and rational target clinical regenerative therapies. However, heterogeneity in cell compartment variable outcomes CRISPR/Cas9 editing make functional interrogation LT-HSCs challenging. Here, we report high efficiency LT-HSC at single-cell resolution using electroporation modified synthetic gRNAs Cas9 protein. Targeted short isoform...
Abstract Background Partially methylated domains (PMDs) are a hallmark of epigenomes in reproducible and specific biological contexts, including cancer cells, the placenta, cultured cell lines. Existing methods for deciding whether PMDs exist sample, as well their identification, few, often tailored to questions, require high coverage samples accurate identification. Results In this study, we outline set axioms that take step towards functional definition PMDs, describe an improved method...
The contribution of basal and luminal cells to cancer progression metastasis is poorly understood. We report generation reporter systems driven by either keratin-14 (K14) or keratin-8 (K8) promoter that not only express a fluorescent protein but also an inducible suicide gene. Transgenic mice the genes in right cell compartments mammary gland epithelia respond treatment with toxins. In addition, we engineered reporters into 4T1 metastatic mouse tumor line demonstrate K14+ cells, K14− K8+,...
Abstract Many cancers are organized as cellular hierarchies sustained by cancer stem cells (CSC), whose eradication is crucial for achieving long-term remission. Difficulties to isolate and undertake in vitro vivo experimental studies of rare CSC under conditions that preserve their original properties currently constitute a bottleneck identifying molecular mechanisms involving coding non-coding genomic regions govern stemness. We focussed on acute myeloid leukemia (AML) paradigm the model...
Gene expression profiling and proteome analysis of normal malignant hematopoietic stem cells (HSCs) point to shared core stemness properties. However, discordance between mRNA protein signatures highlights an important role for post-transcriptional regulation by microRNAs (miRNAs) in governing this critical nexus. Here, we identify miR-130a as a regulator HSC self-renewal differentiation. Enforced impairs B lymphoid differentiation expands long-term HSCs. Integration mass spectrometry...