文章：

扭转骨髓增生异常/骨髓增生性肿瘤的趋势

Turning the tide in myelodysplastic/myeloproliferative neoplasms

原文发布日期：2017-06-23

DOI: 10.1038/nrc.2017.40

类型: Review Article

开放获取: 否

要点：

1. Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are aggressive haematopoietic malignancies that combine myeloid cell dysplasia and proliferation. Recognized entities are juvenile myelomonocytic leukaemia (JMML), chronic myelomonocytic leukaemia (CMML), atypical chronic myeloid leukaemia (aCML) and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).
2. JMML is a disease of young children that occurs as a result of de novo mutations or in the context of hereditary predisposition syndromes. JMML is considered a RASopathy, as somatic or germline mutations that activate the RAS pathway are common founder events whereas secondary mutations are less consistent.
3. MDS/MPN are rare in middle age, but their incidence markedly increases in older individuals, and they can be regarded as one of the malignant conversions of age-related clonal haematopoiesis (ARCH). Mutations in epigenetic regulators may drive the early phases of these diseases, with mutations in signalling genes being acquired later during disease progression.
4. Epigenetic dysregulation in MDS/MPN involves abnormal histone marking caused by inactivation of chromatin modifiers or abnormal DNA methylation resulting from mutations in DNA methyltransferases, splicing regulators or tet methylcytosine dioxygenase 2 (TET2).
5. Hypersensitivity of myeloid progenitors to granulocyte–macrophage colony-stimulating factor (GM-CSF) is a hallmark of JMML and a common feature of CMML, especially when mutations are acquired in signalling genes. An inflammatory bone marrow microenvironment may favour neoplastic at the expense of normal haematopoiesis.
6. Allogeneic stem cell transplantation is the only curative therapy and is commonly used for children with JMML, whereas many adult patients with MDS/MPN are poor transplant candidates owing to age and comorbidities.
7. Hypomethylating agents normalize blood counts in a subset of patients, but rarely restore polyclonal haematopoiesis and have modest effect on survival. Current experimental therapies are focused on inhibiting activated signalling pathways.
8. Novel therapeutic strategies may emerge from a better mechanistic understanding of the interactions between MDS/MPN cells and their stromal microenvironment. The functional capacity of residual normal haematopoietic cells will be crucial to any approach aimed at eliminating the MDS/MPN clone.

要点翻译：

1. 骨髓增生异常综合征/骨髓增殖性肿瘤（MDS/MPN）是一类兼具髓系细胞发育异常和增殖特征的侵袭性造血系统恶性肿瘤。公认的疾病类型包括幼年型粒单核细胞白血病（JMML）、慢性粒单核细胞白血病（CMML）、不典型慢性髓系白血病（aCML）以及伴环状铁粒幼细胞和血小板增多的MDS/MPN（MDS/MPN-RS-T）。
2. JMML是幼童期疾病，由新生突变或遗传易感综合征引发。该疾病被视作RAS信号通路病，因为激活RAS通路的体细胞或种系突变是常见的始动事件，而继发性突变则较少呈现一致性。
3. MDS/MPN在中年人群中罕见，但其发病率随年龄增长显著升高，可视为年龄相关克隆性造血（ARCH）的恶性转化形式之一。表观遗传调控因子突变可能驱动疾病早期进展，信号基因突变则在疾病后期获得。
4. MDS/MPN的表观遗传失调涉及染色质修饰因子失活引发的组蛋白标记异常，以及DNA甲基转移酶、剪接调节因子或Tet甲基胞嘧啶双加氧酶2（TET2）突变导致的DNA甲基化异常。
5. 髓系祖细胞对粒细胞-巨噬细胞集落刺激因子（GM-CSF）的超敏反应是JMML的标志性特征，也是CMML的常见表现，特别是在信号基因发生突变时。炎症性骨髓微环境可能通过抑制正常造血来促进肿瘤增殖。
6. 异基因干细胞移植是唯一根治性疗法，已常规用于JMML患儿，而多数成年MDS/MPN患者因年龄和合并症不适合移植治疗。
7. 去甲基化药物可使部分患者血细胞计数恢复正常，但极少恢复多克隆造血，对生存期的改善有限。当前实验性疗法主要聚焦于抑制激活的信号通路。
8. 通过对MDS/MPN细胞与其基质微环境相互作用的机制研究，或将催生新型治疗策略。在任何旨在清除MDS/MPN克隆的治疗方案中，残留正常造血细胞的功能状态都将至关重要。

英文摘要：

Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are aggressive myeloid malignancies recognized as a distinct category owing to their unique combination of dysplastic and proliferative features. Although current classification schemes still emphasize morphology and exclusionary criteria, disease-defining somatic mutations and/or germline predisposition alleles are increasingly incorporated into diagnostic algorithms. The developing picture suggests that phenotypes are driven mostly by epigenetic mechanisms that reflect a complex interplay between genotype, physiological processes such as ageing and interactions between malignant haematopoietic cells and the stromal microenvironment of the bone marrow. Despite the rapid accumulation of genetic knowledge, therapies have remained nonspecific and largely inefficient. In this Review, we discuss the pathogenesis of MDS/MPN, focusing on the relationship between genotype and phenotype and the molecular underpinnings of epigenetic dysregulation. Starting with the limitations of current therapies, we also explore how the available mechanistic data may be harnessed to inform strategies to develop rational and more effective treatments, and which gaps in our knowledge need to be filled to translate biological understanding into clinical progress.

摘要翻译： 

骨髓增生异常综合征/骨髓增殖性肿瘤（MDS/MPN）是一类具有侵袭性的髓系恶性肿瘤，因其同时具有病态造血和增殖特征而被单独归类。尽管现行分类仍以形态学及排除标准为核心，越来越多的诊断算法已将疾病特异性体细胞突变和/或胚系易感等位基因纳入其中。现有研究提示，其表型主要由表观遗传机制驱动，这些机制反映了基因型、衰老等生理过程与恶性造血细胞及骨髓基质微环境之间复杂相互作用。尽管遗传学知识迅速积累，治疗手段仍缺乏特异性且疗效有限。本文综述MDS/MPN的发病机制，重点探讨基因型与表型的关系及表观遗传失调的分子基础。从当前治疗的局限性出发，我们进一步探讨如何利用现有机制数据指导开发合理且更有效的治疗策略，并指出需填补哪些知识空白才能将生物学认识转化为临床进展。

原文链接：

Turning the tide in myelodysplastic/myeloproliferative neoplasms