Myeloproliferative Neoplasms: JAK2 Signaling Pathway as a Central Target for Therapy
Myeloproliferative Neoplasms: JAK2 Signaling Pathway as a Central Target for Therapy
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DOI：
10.1016/j.clml.2014.06.014
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发表时间：
2014-09-01
影响因子：
2.7
通讯作者：
Vainchenker, Williai
中科院分区：
文献类型：
--
作者：
Pasquier, Florence;Cabagnols, Xenia;Vainchenker, Williai
JAK 2 V617 F突变的发现以及其他遗传异常的发现使得对骨髓增生性肿瘤（MPN）发病机制和管理的理解取得了重要进展。经典折点簇区域-Abelson（BCR-ABL）阴性肿瘤包括3种主要疾病：原发性血小板增多症（ET）、真性红细胞增多症（PV）和原发性骨髓纤维化（PMF）。基因组研究表明，这些疾病比以前认为的更异质，有3个主要实体对应于不同的基因突变：JAK 2疾病，基本上是由于JAK 2 V617 F突变，包括几乎所有的PV和大多数PSV和PMF，这些疾病之间有连续性，骨髓增生性白血病（MPL）和钙网蛋白（CALR）疾病，包括ET和PMF的一部分。所有这些突变导致JAK 2组成型激活。具有JAK 2 V617 F或MPLW 515 L以及具有在遗传性血小板增多症中发现的JAK 2或MPL种系突变的鼠模型已经证明它们是骨髓增殖的驱动因素。然而，在大约15%的Er和PMF中，骨髓增殖驱动突变仍然未知，但似乎也靶向JAK/信号转导和转录激活因子（STAT）途径。然而，参与表观遗传学或剪接的基因中的其他突变也可以存在，并且可以先于或跟随信号传导中的突变。它们参与克隆优势或表型变化，尤其是PMF。它们可能与白血病进展相关，并可能具有重要的预后价值，如额外的性梳样1突变。尽管存在这种异质性，但靶向JAK 2及其信号传导用于治疗是诱人的。然而，在PMF中，腺苷三磷酸（ATP）竞争性JAK 2抑制剂显示出其兴趣，但也显示出其重要的局限性。因此，需要采取其他办法，这将在本审查中讨论。
The discovery of the JAK2V617F mutation followed by the discovery of other genetic abnormalities allowed important progress in the understanding of the pathogenesis and management of myeloproliferative neoplasms (MPN)s. Classical Breakpoint cluster region-Abelson (BCR-ABL)-negative neoplasms include 3 main disorders: essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Genomic studies have shown that these disorders are more heterogeneous than previously thought with 3 main entities corresponding to different gene mutations: the JAK2 disorder, essentially due to JAK2V617F mutation, which includes nearly all PVs and a majority of ETs and PMFs with a continuum between these diseases and the myeloproliferative leukemia (MPL) and calreticulin (CALR) disorders, which include a fraction of ET and PMF. All of these mutations lead to a JAK2 constitutive activation. Murine models either with JAK2V617F or MPLW515L, but also with JAK2 or MPL germ line mutations found in hereditary thrombocytosis, have demonstrated that they are drivers of myeloproliferation. However, the myeloproliferative driver mutation is still unknown in approximately 15% of Er and PMF, but appears to also target the JAK/Signal Transducer and Activator of Transcription (STAT) pathway. However, other mutations in genes involved in epigenetics or splicing also can be present and can predate or follow mutations in signaling. They are involved either in clonal dominance or in phenotypic changes, more particularly in PMF. They can be associated with leukemic progression and might have an important prognostic value such as additional sex comb-like 1 mutations. Despite this hetero geneity, it is tempting to target JAK2 and its signaling for therapy. However in PMF, Adenosine Tri-Phosphate (ATP)-competitive JAK2 inhibitors have shown their interest, but also their important limitations. Thus, other approaches are required, which are discussed in this review.