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 已知干细胞与周围的微环境的相互作用对于两种正常都是必不可少的 发育，以及维持自我更新的成年干细胞，例如造血干细胞（HSC）。 由于癌症经常劫持其进展的发展信号，因此利基驱动的信号很可能是 维持HSC还会影响HSC和早期造血的突变引起的白血病的增长 祖细胞，例如急性髓样白血病（AML）和爆炸危机慢性髓样白血病（BCCML）。尽管 最近的治疗进展，约有75％的AML患者仍然屈服于该疾病，强调了需要更好的 了解疾病进展的机制。虽然很多工作重点是白血病细胞中心 监管机构，微环境在疾病建立和传播中的作用知之甚少。我们的 总体目标是定义白血病 - 基因相互作用在髓样白血病发生上的作用。支持 利基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。由于骨化剂 在白血病骨髓中扩展，这些破骨者可能还会产生癌症支持 微环境。作为识别促进白血病发生的小众驱动信号的替代方法，我们确定了 在LSC上表达的细胞表面抗原，可以使用我们最近的体内充当这些信号的受体 全基因组CRISPR屏幕。我们屏幕鉴定的140个细胞表面基因包括已知的 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 我们可能是癌症特异性的，我们选择了一个新型细胞表面调节剂的子集，其表达高2倍 与我们新的RNA-Seq数据集中的正常HSC相比，在人BCCML LSC中。其中，牛磺酸转运蛋白 SLC6A6（拉紧）特别有趣，因为其高表达与AML的预后不良有关 （TCGA）。使用拉紧 - / - 小鼠，我们发现绷紧的遗传丧失显着损害了体内白血病的生长 与绷紧的+/+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 牛磺酸被骨髓基质细胞的骨氨酸分化上调，牛磺酸被分泌 环境。基于我们的试验研究，表明牛磺酸合成骨构基，这是对 LSC taut表达癌症生长和AML中骨基因生成剂的扩展，我们假设 骨基因生成剂维持LSC并通过分泌牛磺酸来支持白血病进展。现在我们将测试是否绷紧 表达对于疾病小鼠模型中的疾病进展至关重要，也是传播 主要人类白血病。我们还将确定骨基因生成剂是否形成了支持的微环境 白血病通过分泌牛磺酸进展。总的来说，这些研究将确定牛磺酸的作用 骨髓性白血病进展中的骨髓骨髓小裂。从长远来看，这项工作可能会导致 针对支持癌细胞的微环境信号的新疗法的开发。