Novel strategies for the treatment of myelofibrosis driven by recent advances in understanding the role of the microenvironment in its etiology.
Novel strategies for the treatment of myelofibrosis driven by recent advances in understanding the role of the microenvironment in its etiology.
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DOI：
10.12688/f1000research.18581.1
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发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Migliaccio, Anna Rita
中科院分区：
文献类型：
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作者：
Eran, Zimran;Zingariello, Maria;Migliaccio, Anna Rita
骨髓纤维化是费城染色体阴性骨髓增生性肿瘤（mpn）的晚期，其特征是全身炎症、骨髓造血功能衰竭和髓外造血功能的发展，主要发生在脾脏。这种疾病的唯一潜在治疗方法是造血干细胞移植，这一选择可能只提供给那些具有相容供体且年龄和功能状态可能面临其毒性的患者。相比之下，philadelphia阳性mpn可以被由其遗传病变产生的新型BCR-ABL融合蛋白抑制剂显著改变，导致骨髓纤维化发展的分子病变的鉴定尚未转化为可以改变疾病自然史的治疗方法。因此，骨髓纤维化的治疗仍然是一个未满足的临床需求。然而，基因病变的发现引起的兴奋激发了更多的研究，旨在阐明驱动这些肿瘤进入最后阶段的机制。这些研究产生了一种感觉，即骨髓纤维化的治疗将需要针对恶性干细胞克隆及其支持微环境。我们将在这里总结最近在mpn中发现的一些生化改变，以及受这些发现启发而正在研究的新的治疗方法。
Myelofibrosis is the advanced stage of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), characterized by systemic inflammation, hematopoietic failure in the bone marrow, and development of extramedullary hematopoiesis, mainly in the spleen. The only potentially curative therapy for this disease is hematopoietic stem cell transplantation, an option that may be offered only to those patients with a compatible donor and with an age and functional status that may face its toxicity. By contrast, with the Philadelphia-positive MPNs that can be dramatically modified by inhibitors of the novel BCR-ABL fusion-protein generated by its genetic lesion, the identification of the molecular lesions that lead to the development of myelofibrosis has not yet translated into a treatment that can modify the natural history of the disease. Therefore, the cure of myelofibrosis remains an unmet clinical need. However, the excitement raised by the discovery of the genetic lesions has inspired additional studies aimed at elucidating the mechanisms driving these neoplasms towards their final stage. These studies have generated the feeling that the cure of myelofibrosis will require targeting both the malignant stem cell clone and its supportive microenvironment. We will summarize here some of the biochemical alterations recently identified in MPNs and the novel therapeutic approaches currently under investigation inspired by these discoveries.