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Targeting Microenvironmental Signals in Myeloid Malignancies

靶向髓系恶性肿瘤中的微环境信号

基本信息

批准号：
10344681
负责人：
Jeevisha Bajaj
金额：
$ 39.59万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10344681
关键词：
Activities of Daily Living Acute Myelocytic Leukemia Address Adhesives Adult Blast Phase Bone Marrow CRISPR screen Cell Death Cell Line Cell surface Cells Chronic Myeloid Leukemia Clustered Regularly Interspaced Short Palindromic Repeats Data Data Set Development Disease Disease Progression Disease model Endothelial Cells Environment Enzymes Genes Genetic Goals Growth Hematopoiesis Hematopoietic stem cells Human Impairment In Vitro Knowledge Lead Leukemic Cell MLL-AF9 Malignant Neoplasms Mediating Mission Mus Mutation Myelogenous Myeloid Leukemia Myeloproliferative disease Non-Essential Amino Acid Oncogenes Osteoblasts Patients Pilot Projects Prognosis Public Health Receptor Signaling Resistance Role Signal Transduction Stromal Cells Surface Antigens Survival Rate Taurine Testing The Cancer Genome Atlas United States National Institutes of Health Work Xenograft Model acute myeloid leukemia cell adult stem cell base bone cancer cell disability genome-wide in vivo interest knock-down leukemia leukemic stem cell leukemogenesis mouse model myeloid leukemia cell new therapeutic target novel osteogenic osteoprogenitor cell reconstitution self-renewal single-cell RNA sequencing small hairpin RNA stem stem cell self renewal stem cells taurine transporter therapy resistant transcriptome sequencing

项目摘要

ABSTRACT Interactions of stem cells with their surrounding microenvironment are known to be essential for both normal development, and for sustaining self-renewing adult stem cells, such as the hematopoietic stem cells (HSCs). Since cancers often hijack developmental signals for their progression, it is likely that niche-driven signals that sustain HSCs also influence the growth of leukemias arising from mutations in HSCs and early hematopoietic progenitors, such as acute myeloid leukemia (AML) and blast crisis chronic myeloid leukemia (bcCML). Despite recent advances in treatment, ~75% of AML patients still succumb to the disease, highlighting the need to better understand mechanisms of disease progression. While much work has focused on leukemia cell-intrinsic regulators, the role of the microenvironment in disease establishment and propagation is poorly understood. Our overall goal is to define the role of leukemia-niche interactions on myeloid leukemogenesis. In support of a functional role of the niche in disease progression, our work has shown that adhesive interaction of AML with endothelial cells is critical to maintain the therapy-resistant leukemia stem cells (LSCs). Since osteoprogenitors expand in the leukemic bone marrow, it is possible that these osteoprogenitors also create a cancer-supporting microenvironment. As an alternate to identifying niche-driven signals promoting leukemogenesis, we determined cell surface antigens expressed on LSCs that can act as receptors for these signals using our recent in vivo genome-wide CRISPR screen. The 140 cell surface genes identified by our screen included those known to promote leukemia growth (e.g., Cd47, Cd157) and novel regulators of leukemia progression. To focus on signals likely to be cancer-specific, we selected a subset of novel cell-surface regulators with 2-fold higher expression in human bcCML LSCs compared to normal HSCs in our new RNA-seq dataset. Of these, the taurine transporter SLC6A6 (TauT) is of particular interest since its high expression is associated with poor prognosis in AML (TCGA). Using TauT-/- mice, we find that genetic loss of TauT significantly impairs leukemia growth in vivo as compared to TauT+/+. Our key preliminary data show that enzymes for synthesis of the non-essential amino acid taurine are upregulated with osteolineage differentiation of bone marrow stromal cells, and taurine is secreted in the environment. Based on our pilot studies showing taurine synthesis by osteoprogenitors, a requirement for LSC TauT expression for cancer growth, and expansion of osteoprogenitors in AML, we hypothesize that osteoprogenitors sustain LSCs and support leukemia progression by secreting taurine. We will now test if TauT expression is essential for disease progression in mouse models of disease, as well as for the propagation of primary human leukemias. We will also determine if osteoprogenitors form a supportive microenvironment for leukemia progression by secreting taurine. Collectively, these studies will establish the role of taurine from the bone marrow osteolineage niche in myeloid leukemia progression. In the long term this work may lead to development of new therapies targeting microenvironmental signals supporting cancer cells.

摘要