Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation
Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation
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DOI：
10.1172/jci71861
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发表时间：
2014-02-01
影响因子：
15.9
通讯作者：
Raslova, Hana
中科院分区：
文献类型：
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作者：
Bluteau, Dominique;Balduini, Alessandra;Raslova, Hana
锚蛋白重复结构域26（ANKRD 26）的5' UTR中的点突变与家族性血小板减少症2（THC 2）和白血病的易感性相关。在这里，我们确定了ANKRD 26相关血小板减少症的潜在机制。使用从THC 2患者和健康受试者中分离的巨核细胞（MK），我们证明ANKRD 26的5' UTR中的THC 2相关突变导致runt相关转录因子1（RUNX 1）和朋友白血病整合1转录因子（FLI 1）结合的丧失。来自健康受试者的RUNX 1和FLI 1在5' UTR处的结合导致ANKRD 26在巨核细胞生成和血小板发育的晚期阶段沉默。我们发现在分离的MK中持续的ANKRD 26表达增加了通过血小板生成素/骨髓增生性白血病病毒癌基因（MPL）途径的信号传导，并损害了MK的前血小板形成。重要的是，我们证明了ERK抑制完全挽救了体外前血小板形成缺陷。我们的数据确定了与异常MAPK信号相关的家族性血小板减少症THC 2的发展机制。
Point mutations in the 5' UTR of ankyrin repeat domain 26 (ANKRD26) are associated with familial thrombocytopenia 2 (THC2) and a predisposition to leukemia. Here, we identified underlying mechanisms of ANKRD26-associated thrombocytopenia. Using megakaryocytes (MK) isolated from THC2 patients and healthy subjects, we demonstrated that THC2-associated mutations in the 5' UTR of ANKRD26 resulted in loss of runt-related transcription factor 1 (RUNX1) and friend leukemia integration 1 transcription factor (FLI1) binding. RUNX1 and FLI1 binding at the 5' UTR from healthy subjects led to ANKRD26 silencing during the late stages of megakaryopoiesis and blood platelet development. We showed that persistent ANKRD26 expression in isolated MKs increased signaling via the thrombopoietin/myeloproliferative leukemia virus oncogene (MPL) pathway and impaired proplatelet formation by MKs. Importantly, we demonstrated that ERK inhibition completely rescued the in vitro proplatelet formation defect. Our data identify a mechanism for development of the familial thrombocytopenia THC2 that is related to abnormal MAPK signaling.