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Defining malignant hematopoiesis via single-cell multi-omics

通过单细胞多组学定义恶性造血

基本信息

批准号：
10018257
负责人：
Seung Ha Nam
金额：
$ 42.38万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10018257
关键词：
Admixture Advisory Committees Affect Anatomy Appointment Biochemical Biological Assay Biomedical Research Blood Blood Cells Bone Marrow CD34 gene Cell Cycle Cell physiology Cell surface Cells Chromatin Clinical Communities Complex Core Facility DNA DNA Sequence Alteration Data Dependence Development Diagnostic Disease Environment Environmental Risk Factor Epigenetic Process Exhibits Faculty Funding Gene Mutation Genes Genetic Genetic Transcription Genome Genomic medicine Genomics Genotype Hematological Disease Hematopathology Hematopoiesis Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Human Immune Immunologic Factors Individual Inorganic Chemistry Institutes Intrinsic factor Investigation Laboratories Lead Link MPL gene Malignant - descriptor Medicine Memorial Sloan-Kettering Cancer Center Mentors Modernization Molecular Molecular Genetics Morphology Mutate Mutation Myelogenous Myeloproliferative disease NF-kappa B Nature Neoplastic Processes New York Outcome Output Pathology Pathway interactions Patients Peer Review Physicians Population Process Protein Secretion Proteins Publications Research Research Personnel Research Training Resources Sampling Scientist Signal Transduction Somatic Mutation Specimen Supervision T-Lymphocyte Technology Testing Therapeutic Intervention Tissues Training Translational Research Trees United States National Institutes of Health Ursidae Family biobank calreticulin cell type clinical phenotype college cytokine disease phenotype doctoral student driver mutation epigenome epigenomics hematopoietic differentiation immunomodulatory therapies improved innovation insight medical schools medical specialties molecular array mouse model multidisciplinary multiple omics mutant neoplastic neoplastic cell next generation novel personalized medicine progenitor programs response single cell sequencing stem cells targeted treatment tool transcription factor transcriptome transcriptomics undergraduate student

项目摘要

PROJECT SUMMARY / ABSTRACT Clonal blood differentiation through the acquisition of somatic mutations result in abnormal accumulation of blood components and clinically manifest as myeloid disorders. The study of how these somatic mutations perturb the differentiation trajectories in human hematopoiesis is often challenged by the admixture of normal hematopoietic cells with the neoplastic cells that cannot be distinguished by cell surface markers. To overcome this limitation, we developed a novel single-cell multi-omics Genotyping of Transcriptomes (GoT) platform that directly links somatic genotypes with transcriptomes of thousands of single cells. Thus, GoT enabled the comparison of mutant and wildtype cells within the same sample in the context of progenitor identities, thereby turning the co-mingling of mutant and wildtype hematopoiesis from a limitation to an advantage. As proof of principle, GoT was applied to CD34+ progenitor cells from patients with calreticulin- mutated myeloproliferative neoplasms (MPN), revealing key pathways that were aberrantly activated in the mutant cells, such as a robust unfolded protein response in the megakaryocytic progenitors, on the one way, and NF-KB pathway in stem cell-enriched populations, on the other. Overall, GoT revealed that the transcriptional impact of calreticulin mutations is highly variable as a function of progenitor identity – which bears significant implications for therapy by enabling the discovery of targetable pathways specific to the earliest stem cells. Thus, to demonstrate the cell identity-dependency across other key driver mutations, as a fundamental concept in myeloid disorders, I will apply GoT to thrombopoietin receptor-mutated progenitor cells and to clonally-diverse cells from MPN samples (Aim 1). Next, in order to define cell extrinsic determinants of somatic mutation impact, I will determine the immune niche interactions with calreticulin-mutant and wildtype progenitor cells, as well as the impact of immunomodulatory therapy on these interactions (Aim 2). Finally, I will test the hypothesis that the cell’s epigenome precedes the cell identity-dependency of somatic mutation effects, by developing and applying a novel single-cell platform that integrates somatic genotyping with chromatin accessibility states of progenitor cells (Aim 3). Thus, I will define the genetic, epigenetic, transcriptional and environmental factors that culminate in the clinical output of somatic mutations in human hematopoiesis. These studies will, therefore, unveil not only fundamental concepts in clonal hematopoietic differentiation but also specific targets for therapeutic intervention.

项目摘要/摘要