HSC-Independent Mechanisms Underlying JMML

项目总结/摘要 青少年粒单核细胞白血病（JMML）是最常见的骨髓增生性肿瘤（MPN）， 儿童期，往往发生在4岁以下的幼儿中。JMML传统上 在一些实施方案中，所述抗体被表征为由于NF 1、CBL、KRAS、NRAS或PTPN 11中的突变而被Ras驱动。传统 细胞毒性化疗药物对JMML无效，唯一的治疗方式是同种异体 造血干细胞移植与其他MPN不同，JMML很少进展到爆炸危机;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的复发率明显高于接受同种异体干细胞移植的个体。 移植用于慢性期的慢性粒细胞白血病（CML）（约7%的白血病复发）， 暗示JMML发育的强造血干细胞（HSC）独立成分， 进展 我们设想了两种不同的机制，可能占一个HSC独立的手段JMML复发 异基因HSC移植后。首先，JMML起始的恶性细胞可在胚胎期出现， 在HSC之前和独立于HSC发展，并且在出生后作为自我补充的恶性肿瘤持续存在。 组织巨噬细胞或者，无论JMML细胞的来源如何， 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，允许残留的白血病细胞胜过正常移植物，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的Cre重组酶系统，这将允许 卵黄囊限制性表达的常见JMML突变，Shp 2D 61 Y，以确定是否卵黄囊限制性表达， 癌基因的表达足以促进MPN的出生后发育。此外，我们将检查抑制是否 促炎蛋白PI 3 K p110δ的表达，改善了归巢、植入、扩张和骨髓 WT供体细胞分化为患病的表达Shp 2D 61 Y的受体。

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.