Targeting Microenvironmental Signals in Myeloid Malignancies

靶向髓系恶性肿瘤中的微环境信号

• 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
• 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

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.

抽象的 众所周知，干细胞与其周围微环境的相互作用对于正常细胞和微环境至关重要。 发育，以及维持自我更新的成体干细胞，例如造血干细胞（HSC）。 由于癌症经常劫持发展信号以促进其进展，因此利基驱动的信号很可能 维持 HSC 也会影响由 HSC 突变和早期造血功能引起的白血病的生长 祖细胞，例如急性髓系白血病 (AML) 和急变慢性髓系白血病 (bcCML)。尽管 近年来治疗取得进展，约 75% 的 AML 患者仍死于该疾病，这凸显了需要更好的治疗方法 了解疾病进展的机制。虽然很多工作都集中在白血病细胞内在 对于调节者而言，微环境在疾病建立和传播中的作用知之甚少。我们的 总体目标是确定白血病-生态位相互作用对髓系白血病发生的作用。支持一个 该生态位在疾病进展中的功能作用，我们的工作表明 AML 与 内皮细胞对于维持耐药性白血病干细胞（LSC）至关重要。由于骨祖细胞 在白血病骨髓中扩张，这些骨祖细胞也可能产生支持癌症的细胞 微环境。作为识别促进白血病发生的利基驱动信号的替代方法，我们确定 使用我们最近的体内研究，LSC 上表达的细胞表面抗原可以充当这些信号的受体 全基因组 CRISPR 筛选。我们的筛选鉴定出 140 个细胞表面基因，其中包括那些已知的 促进白血病生长（例如 Cd47、Cd157）和白血病进展的新型调节剂。专注于信号 由于可能具有癌症特异性，我们选择了表达量高出 2 倍的新型细胞表面调节因子子集 在我们的新 RNA-seq 数据集中，人类 bcCML LSC 与正常 HSC 进行了比较。其中，牛磺酸转运蛋白 SLC6A6 (TauT) 特别令人感兴趣，因为它的高表达与 AML 的不良预后相关 （TCGA）。使用 TauT-/- 小鼠，我们发现 TauT 基因缺失会显着损害体内白血病的生长，如下所示： 与 TauT+/+ 相比。我们的关键初步数据表明，用于合成非必需氨基酸的酶 牛磺酸随着骨髓基质细胞的骨谱系分化而上调，牛磺酸分泌于 环境。根据我们的初步研究显示，骨祖细胞合成牛磺酸，这是 LSC TauT 表达与癌症生长和 AML 中骨祖细胞的扩张有关，我们假设 骨祖细胞通过分泌牛磺酸维持 LSC 并支持白血病进展。我们现在将测试 TauT 表达对于小鼠疾病模型的疾病进展以及传播至关重要 原发性人类白血病。我们还将确定骨祖细胞是否形成支持性微环境 通过分泌牛磺酸促进白血病进展。总的来说，这些研究将确定牛磺酸的作用 髓系白血病进展中的骨髓骨谱系生态位。从长远来看，这项工作可能会导致 开发针对支持癌细胞的微环境信号的新疗法。