PDF(Pubmed)
Abstract：
Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss-of-function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells also demonstrated sensitivity of SH2B3-mutated hematopoietic progenitor cells to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.
摘要：
五个经典Ras途径基因(NF1，NRAS，KRAS,PTPN11和CBL）在近90％的青少年粒单核细胞白血病（JMML）患者中检测到，儿童早期经常致命的恶性肿瘤。在这份报告中,我们描述了7例诊断为SH2B3突变JMML的患者，包括五名被发现患有心脏病的患者，基因的功能缺失突变。SH2B3编码衔接蛋白LNK，Ras通路上游正常造血的负调节因子。这些突变被鉴定为种系，躯体或两者的组合。LNK功能丧失,在其他骨髓性恶性肿瘤中也观察到了这一点，由于细胞因子超敏反应和JAK/STAT信号通路的激活，导致造血细胞异常增殖。诱导多能干细胞衍生的JMML样造血祖细胞(HPCs)的体外研究也证明了SH2B3-突变的HPCs对JAK抑制的敏感性。最后,我们描述了2例JMML和SH2B3突变患者接受JAK1/2抑制剂鲁索利替尼治疗.该报告扩展了JMML中起始突变的范围，并提高了在SH2B3突变患者中靶向JAK/STAT途径的可能性。
