HSC-Independent Mechanisms Underlying JMML

JMML 背后的 HSC 独立机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要幼年型粒单核细胞白血病 (JMML) 是最常见的骨髓增生性肿瘤 (MPN) 传统上，JMML 多发生于 4 岁以下的幼儿。由于 NF1、CBL、KRAS、NRAS 或 PTPN11 突变而被定性为 Ras 驱动。细胞毒性化疗药物对 JMML 无效，唯一的治疗方式是同种异体化疗与其他 MPN 不同，JMML 很少进展为急变期；死亡是由于髓外肿瘤细胞扩张导致器官衰竭、呼吸衰竭、出血或值得注意的是，在同种异体干细胞移植后，50% 的儿童死于白血病复发。 JMML 的复发率明显高于接受同种异体干细胞的个体慢性粒细胞白血病 (CML) 慢性期移植（约 7% 白血病复发），暗示 JMML 发展中存在一个强烈的造血干细胞 (HSC) 独立成分，进展。我们设想两种不同的机制可能解释 JMML 复发的独立于 HSC 的方式同种异体 HSC 移植后，首先，JMML 起始恶性细胞可能在胚胎期间出现。先于 HSC 发育并独立于 HSC，并在出生后持续作为自我补充的恶性细胞或者，无论 JMML 细胞的来源如何，其高炎症性质。 JMML可能会破坏骨髓微环境，抑制正常供体细胞的扩增移植后，残留的白血病细胞能够战胜正常的移植物，并导致白血病复发。为了解决这些可能性，我们将使用他莫昔芬诱导型 Cre 重组酶系统，该系统将允许常见 JMML 突变 Shp2D61Y 的卵黄囊限制表达，以确定卵黄囊是否限制癌基因表达足以促进 MPN 的产后发展。此外，我们将检查是否受到抑制。促炎蛋白 PI3K p110δ 的表达可改善归巢、植入、扩张和骨髓细胞 WT 供体细胞分化为表达 Shp2D61Y 的患病受体。