HSC-Independent Mechanisms Underlying JMML

JMML 背后的 HSC 独立机制

• 批准号: 9178088
• 负责人: REBECCA J. CHAN
• 金额: $ 16.97万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178088
• 关键词: 4 year old; Accounting; Acute; Address; Adult; Allogenic; Biochemical; Biological Assay; Blast Phase; Bone Marrow; CBL gene; Cell Lineage; Cells; Characteristics; Child; Childhood; Chronic Myeloid Leukemia; Chronic Phase; Clinical; Coupled; Cytomegalovirus; Development; Disease; Embryo; Embryonic Development; Engraftment; Extramedullary; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemorrhage; Homing; Human Herpesvirus 4; Hypersensitivity; Immune; Individual; Infection; Inflammation; Inflammatory; Juvenile Myelomonocytic Leukemia; KRAS2 gene; Knock-in; Laboratories; Malignant - descriptor; Modality; Monitor; Mus; Mutation; Myelogenous; Myeloid Cells; Myeloproliferative disease; NF1 gene; Nature; Oncogenes; Oncogenic; Organ failure; PTPN11 gene; Patients; Peripheral; Production; Protein Tyrosine Phosphatase; Proteins; Publishing; Reactive Oxygen Species; Regimen; Relapse; Residual state; Resistance; Respiratory Failure; Series; Simplexvirus; Stem cell transplant; Syndrome; System; Tamoxifen; Tissues; Transplantation; Validation; Virus Diseases; Yolk Sac; cancer cell; chemotherapeutic agent; chemotherapy; cytotoxic; gain of function; improved; in vivo; inhibitor/antagonist; innovation; leukemia; macrophage; mortality; mouse model; neoplastic cell; neutrophil; postnatal; progenitor; recombinase

PROJECT SUMMARY/ABSTRACT Juvenile myelomonocytic leukemia (JMML) is the most common myeloproliferative neoplasm (MPN) in childhood, and tends to occur in very young children less than 4 years of age. JMML is traditionally characterized as being Ras-driven due to mutations in NF1, CBL, KRAS, NRAS, or PTPN11. Traditional cytotoxic chemotherapeutic agents are ineffective in JMML, and the only curative modality is allogeneic hematopoietic stem cell transplantation. Unlike other MPNs, JMML rarely progresses to blast crisis; rather, mortality is due to extramedullary tumor cell expansion leading to organ failure, respiratory failure, bleeding, or infection. Notably, following allogeneic stem cell transplant, 50% of children succumb to leukemia relapse. This relapse rate in JMML is substantially higher than that of individuals who receive allogeneic stem cell transplant for chronic myelogenous leukemia (CML) in chronic phase (approximately 7% leukemia relapse), implicating a strong hematopoietic stem cell (HSC)-independent component of JMML development and progression. We envision two distinct mechanisms that potentially account for a HSC-independent means of JMML relapse after allogeneic HSC transplant. First, the JMML-initiating malignant cells may emerge during embryonic development prior to and independently from HSCs, and persist postnatally as self-replenishing malignant tissue macrophages. Alternatively, regardless of the origin of the JMML cells, the hyperinflammatory nature of JMML may damage the bone marrow microenvironment, prohibiting the expansion of normal donor cells following transplant, permitting residual leukemia cells to outcompete the normal graft, and leading to leukemia relapse. To address these possibilities, we will use the tamoxifen-inducible Cre recombinase system, which will permit yolk sac-restricted expression of the common JMML mutation, Shp2D61Y, to determine if yolk sac-restricted oncogene expression is sufficient for the post-natal development of MPN. Further, we will examine if inhibition of the pro-inflammatory protein, PI3K p110δ, improves homing, engraftment, expansion, and myeloid differentiation of WT donor cells into diseased, Shp2D61Y-expressing recipients.

项目摘要/摘要 幼年粒单核细胞白血病(JMML)是我国最常见的骨髓增生性肿瘤(MPN) 儿童时期发病，往往发生在4岁以下的幼儿。JMML是传统的 特征为由于NF1、CBL、KRAS、NRAS或PTPN11的突变而由RAS驱动。传统型 细胞毒性化疗药物对JMML无效，唯一的治疗方法是异基因治疗 造血干细胞移植。与其他MPN不同，JMML很少发展到爆发危机；相反， 死亡是由于髓外肿瘤细胞扩张导致器官衰竭、呼吸衰竭、出血或 感染。值得注意的是，在异基因干细胞移植后，50%的儿童死于白血病复发。 JMML患者的复发率明显高于接受异基因干细胞移植的患者 慢性粒细胞白血病(CML)慢性期移植(约7%白血病复发) 暗示JMML的发育和发育过程中存在一个强大的造血干细胞(HSC)非依赖性组件 进步。 我们设想了两种不同的机制，它们潜在地解释了JMML复发的HSC非依赖性手段 同种异体造血干细胞移植后。首先，启动JMML的恶性细胞可能在胚胎期间出现 在HSC之前和独立于HSCs发展，并在出生后作为自我补充的恶性持续存在 组织巨噬细胞。或者，无论JMML细胞的来源如何，JMML的高炎性本质 JMML可能会破坏骨髓微环境，阻止正常供体细胞的扩张 移植后，允许残留的白血病细胞比正常移植物竞争，并导致白血病 旧病复发。 为了解决这些可能性，我们将使用他莫昔芬诱导的Cre重组酶系统，这将允许 常见JMML突变Shp2D61Y卵黄囊限制性表达的研究 癌基因的表达为MPN的出生后发育提供了充足的条件。此外，我们将检查抑制是否 促炎症蛋白，PI3K p110δ，改善归巢、植入、扩张和髓系 将WT供体细胞分化为表达Shp2D61Y的病态受体。