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Backtracking Leukemia-Typical Somatic Alterations in Cord Blood at Single-cell Resolution

以单细胞分辨率回溯脐带血中白血病典型体细胞改变

基本信息

批准号：
10693149
负责人：
Adam De Smith
金额：
$ 55.68万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693149
关键词：
15 year old Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Architecture Biological Assay Birth Birth Records Birth Weight Blood Blood Cells Blood specimen CBFA2T1 gene CD34 gene Cause of Death Cell Separation Cells Cesarean section Child Childhood Acute Lymphocytic Leukemia Childhood Leukemia Cohort Studies DNA Sequence Alteration Data Development Diagnostic Dryness ETV6 gene Eligibility Determination Ethnic Origin Etiology Event Face Frequencies Future Gene Expression Gene Expression Profile Gene Fusion Generations Genetic Genotype Goals Hematopoietic Immunophenotyping Lesion MLL gene Malignant Childhood Neoplasm Measures Morbidity - disease rate Mutation Natural History Neonatal Neonatal Leukemia Neonatal Screening Newborn Infant Parental Ages Patients Pediatric Oncology Group Perinatal Point Mutation Population Preleukemia Prevention Preventive RUNX1 gene Race Resolution Risk Factors Sampling Somatic Mutation Sorting Spottings Surveys Survivors Testing Umbilical Cord Blood cell type digital disorder risk driver mutation epidemiology study genetic risk factor genome sequencing high risk in utero indexing individualized prevention leukemia leukemogenesis prenatal progenitor risk prediction model screening sex stem transcriptome sequencing transcriptomics tumor whole genome

项目摘要

Abstract Acute leukemia is the most common childhood cancer, and remains one of the leading causes of death in children under 15 years of age. Prevention, therefore, remains the ultimate goal. An essential part of future preventive efforts will involve identifying children harboring preleukemic clones at birth. Several leukemia-initiating genetic lesions have been shown to arise prenatally; however, many other leukemia-initiating lesions have not been examined at birth. Several critical questions remain to be answered: 1) What subtypes and what proportion of childhood leukemia develops in utero? 2) What is the specific cell(s) of origin in which preleukemic clones arise? and 3) Are some newborns more prone to developing leukemia-initiating lesions than others? In this project, we will answer these questions, with a focus on the ~70% of patients with known translocation or point mutation driver events. This project has three main aims. Aim 1: To identify the presence and clonal frequency of prenatal leukemia-initiating lesions at birth. We will obtain matched cord blood (CB) and diagnostic leukemia samples from ~250 childhood leukemia patients in the Children’s Oncology Group Project:Every Child study. Backtracking will focus on ~182 patients with translocation/mutation-driven subtypes. We derive patient-specific somatic mutations from tumor profiling, then use droplet digital PCR (ddPCR) in flow-sorted CB cells to confirm the presence and frequency of leukemia-initiating lesions at birth, and at different hematopoietic stages. We will also use ddPCR to backtrack lesions in available newborn dried bloodspots (N ~45). Aim 2: To determine the cell of origin of leukemia- initiating lesions, the transcriptomic changes from preleukemia to overt leukemia, and whether secondary mutations arise prenatally, across childhood leukemia subtypes. In 50 childhood leukemia patients where CB ddPCR is positive we will conduct single-cell TARGET-seq on flow-sorted cell populations to simultaneously detect the presence of each patient-specific leukemia-initiating events, secondary mutations, and gene expression in genotypically- and immunophenotypically-defined populations at a single cell level. Aim 3: To determine whether the presence and frequency of preleukemic clones correlate with known risk factors for leukemia. Demographic, perinatal, and genetic risk factors for childhood leukemia will be obtained through parental survey, birth records, and sequencing data. For overall ALL and AML, and for common subtypes, we will test for association between risk factors and the presence and clonal frequency of preleukemic clones at birth, as measured in Aim 1. Identifying a specific cell of origin of preleukemic genomic alterations, and their frequency in neonatal blood, will shed light on childhood leukemia etiology and have important implications for precision prevention efforts. This study will identify key steps required for leukemogenesis by directly comparing the genetic and transcriptomic architecture of preleukemic CB to the subsequent full-blown leukemia. Results will provide a platform for development of large- scale population testing of preleukemic clones in healthy newborns and will enable the first cohort studies examining progression from pre- to overt leukemia.

摘要