权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting dormant leukemia-initiating cells in T-cell acute lymphoblastic leukemia

靶向 T 细胞急性淋巴细胞白血病中的休眠白血病起始细胞

基本信息

批准号：
10538633
负责人：
Kevin O'Connor
金额：
$ 3.49万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2020-12-23 至 2024-12-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10538633
关键词：
Acute T Cell Leukemia Biological Assay Calcineurin Cell Cycle Cell Separation Cell physiology Cell surface Cells Chemoresistance Child Childhood Acute Lymphocytic Leukemia Childhood Precursor T Lymphoblastic Leukemia Data Databases Development Diagnosis Disease Disease remission Exhibits Failure Foundations Frequencies Gene Expression Profile Genes Genetic Transcription Genetically Engineered Mouse Goals Hematopoiesis Hematopoietic stem cells Heterogeneity Human Immunophenotyping Impairment Label Laboratories Leukemic Cell Mediating Modeling Mus NOTCH1 gene Parents Pathway interactions Patients Population Prognosis Proliferating Radiation therapy Recurrent disease Refractory Disease Relapse Reporting Resistance Role Sampling Signal Pathway Signal Transduction Sorting T-Lymphocyte T-Lymphocyte Subsets TAL1 gene Testing Therapeutic Thymus Gland Transgenic Organisms Transplantation WNT Signaling Pathway Work acute T-cell lymphoblastic leukemia cell beta catenin cell regeneration chemotherapy differential expression genetic signature hematopoietic stem cell quiescence hematopoietic stem cell self-renewal human disease in vivo insight leukemia leukemia initiating cell leukemia relapse leukemia treatment leukemic stem cell leukemogenesis mouse model overexpression patient derived xenograft model prevent progenitor programs receptor regeneration potential single-cell RNA sequencing stem cell function stem cell proliferation stem cells targeted treatment therapy resistant thymocyte transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Therapy resistance is a major barrier to long term remission in pediatric T-cell acute lymphoblastic leukemia (T- ALL). The prognosis for children with relapsed or refractory disease is dismal. Leukemia-initiating cells (L-ICs) regenerate disease upon transplantation into mice. They also recapitulate the immunophenotypic complexity of the parent leukemia supporting that, as in normal hematopoiesis, there is a cellular hierarchy among leukemic cells. Our laboratory has previously demonstrated that the L-IC is a committed thymocyte progenitor and resides in the leukemic DN3 population, however, only a fraction of DN3 cells can give rise to disease. L-ICs rely on NOTCH1-induced MYC signaling for survival. Recent studies identified dormant, therapy resistant L-ICs in both murine models and T-ALL patient samples. The role of cell cycle restriction in L-IC latency is incompletely understood. In an effort to uncover pathways that govern L-IC function, we performed single cell RNA- sequencing on thymocytes at varying stages of T-cell leukemogenesis using our transgenic Tal1/Lmo2 model. This approach identified a dormant DN3 cluster, marked by low Ki67 expression, which is observed in other murine T-ALL samples. Dormant DN3 cells exhibit high Notch1, but low Myc expression. The transcriptional signature of these cells shows enrichment of genes previously implicated in leukemia initiation or leukemia stem cell function. Dormant DN3 cells show enrichment of the non-canonical Wnt receptor Ryk, which is reported to maintain hematopoietic stem cell self-renewal by limiting proliferation and promoting quiescence. RYK is overexpressed in primary pediatric T-ALL and in Tal1/Lmo2-induced murine T-ALL compared to healthy thymus. This indicates that RYK may not be restricted to this rare subpopulation and moreover, there may be a therapeutic window for RYK inhibition in relapsed T-ALL. The central hypothesis of this proposal is that dormant DN3 cells are quiescent L-ICs that retain proliferative and differentiative capacity, which permits their therapy tolerance and subsequent expansion during relapse. This proposal will identify a gene signature of dormant DN3 cells and uncover the potential role of these cells in T-ALL relapse by evaluating their L-IC function and chemoresistance (Aim 1). Aim 2 will define the non-canonical WNT/RYK signaling network in T-ALL and uncover the role of these pathways in dormant DN3 cells and L-IC function by testing whether inhibition of RYK reduces the L-IC frequency of murine and patient T-ALL cells. Collectively, these studies will provide critical insight to T- ALL heterogeneity and will lay the foundation for development of L-IC targeted therapy for relapsed disease.

项目总结/文摘