Identification of biomarker(s) of monocyte precursors in human bone marrow

人骨髓中单核细胞前体生物标志物的鉴定

• 批准号: 10264681
• 负责人: Raul Braylan
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264681
• 关键词: Acute; Acute Myelocytic Leukemia; Acute leukemia; Antigens; Autoimmune Diseases; Benign; Biological Markers; Blood; Bone Marrow; CD34 gene; Cell Separation; Cells; Chronic Myelomonocytic Leukemia; Classification; Clinical; DNA Sequence Alteration; Dendritic Cells; Detection; Development; Diagnosis; Diagnostic; Elements; Flow Cytometry; Human; In Vitro; Laboratories; Leukocytes; Lymphoblastic Leukemia; Lymphocyte; Lymphoid; Marrow; Monocytic leukemia; Monocytosis; Mus; Myelogenous; Myeloid Leukemia; Nature; Neoplastic Processes; Nomenclature; Normal Cell; Phenotype; Proto-Oncogene Protein c-kit; RNA marker; Sorting - Cell Movement; Techniques; Technology; Therapeutic; Tissues; Translating; Travel; Uncertainty; base; biomarker identification; chronic infection; chronic leukemia; cytochemistry; design; granulocyte; leukemia; macrophage; monoblast; monocyte; neoplastic; neoplastic cell; response; transcriptome; transcriptome sequencing; treatment stratification

Monocytes originate in the bone marrow, and travel through the blood to tissues where they become macrophages or dendritic cells. An increased number of monocytes in the blood (monocytosis) occurs in response to chronic infections, autoimmune disorders, and in certain acute and chronic leukemias. Among the leukemias, various types have been recognized, including acute myelomonocytic, acute monoblastic, acute monocytic, and chronic myelomonocytic leukemia. Other terms, such as acute myeloid leukemia with monocytic differentiation, are also used, adding to the already confusing nomenclature. At present, the main techniques utilized in the identification of monocytic lineage are cytomorphology, cytochemistry and flow cytometry, but the exact delineation of the various types of acute and chronic leukemias and their differentiation from benign monocytosis has remained a serious challenge. This is largely because the identification of blastic, dysplastic or reactive monocytes is far from being accurate or precise. Genetic mutations are often observed in monocytic leukemias but again, they are not specific since they are observed in other neoplastic processes. This uncertainty translates into serious diagnostic or even therapeutic decisions, which are often based on determining the nature of a monocytic proliferation, or an accurate blast count. Most non-monocytic acute leukemias (myeloid or lymphoid) recapitulate the phenotype of early normal precursors and thus express highly informative antigens like CD34, CD117, or TdT. These leukemic-associated antigens are not specific for the neoplastic cells. They are simply antigens that are expressed in early stages of normal cell development in the marrow. It is very likely that markers expressed in early stages of monocyte development could as well serve as proper identifiers for blasts in monocytic leukemias. However, in contrast to granulocytic or lymphoid leukemias, there are no single markers that allow the unequivocal recognition of leukemic monocytes. This is largely because human monocyte precursors have not been adequately characterized. Based on preliminary observations, we propose to identify and purify putative monocytic precursor from normal human bone marrow using flow cytometry/sorting and: 1. Demonstrate that they are indeed monocytic precursors and, 2. Compare their transcriptome with that of all other cells in the marrow using the RNAseq technique in order to identify specific RNA markers (and eventually products) that would allow their identification. Appropriate recognition of monocyte precursors (and likely monocytic blasts) should enable us to establish better diagnosis and classification of monocytic leukemias and help designing proper therapeutic stratification.

单核细胞起源于骨髓，并通过血液到达组织，在那里它们变成巨噬细胞或树突细胞。 血液中单核细胞数量增加（单核细胞增多症）是由于慢性感染、自身免疫性疾病以及某些急性和慢性白血病而发生的。 在白血病中，已经认识到各种类型，包括急性粒单核细胞白血病、急性单核细胞白血病、急性单核细胞白血病和慢性粒单核细胞白血病。 其他术语，如单核细胞分化的急性髓性白血病，也被使用，增加了已经混乱的命名。 目前，用于鉴定单核细胞谱系的主要技术是细胞形态学、细胞化学和流式细胞术，但各种类型的急性和慢性白血病的准确划分以及它们与良性单核细胞增多症的鉴别仍然是一个严峻的挑战。 这在很大程度上是因为母细胞、发育不良或反应性单核细胞的鉴定远不准确或精确。 基因突变经常在单核细胞白血病中观察到，但同样，它们不是特异性的，因为它们在其他肿瘤过程中观察到。 这种不确定性转化为严重的诊断甚至治疗决定，这通常是基于确定单核细胞增殖的性质或准确的原始细胞计数。 大多数非单核细胞急性白血病（髓系或淋巴系）重现了早期正常前体细胞的表型，因此表达高度信息性抗原，如CD 34、CD 117或TdT。 这些白血病相关抗原对肿瘤细胞没有特异性。 它们只是在骨髓中正常细胞发育的早期阶段表达的抗原。 在单核细胞发育的早期阶段表达的标记物很可能也可以作为单核细胞白血病中原始细胞的适当标识符。 然而，与粒细胞或淋巴样白血病相反，没有单一的标记物可以明确识别白血病单核细胞。 这在很大程度上是因为人单核细胞前体尚未得到充分表征。 基于初步的观察，我们建议使用流式细胞术/分选从正常人骨髓中鉴定和纯化推定的单核细胞前体，并且：1。证明它们确实是单核细胞前体，2。使用RNAseq技术将它们的转录组与骨髓中所有其他细胞的转录组进行比较，以确定允许它们识别的特定RNA标记物（以及最终产物）。 正确识别单核细胞前体细胞（以及可能的单核细胞母细胞）应使我们能够建立更好的诊断和分类单核细胞白血病，并帮助设计适当的治疗分层。