Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia.
Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia.
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DOI：
10.3324/haematol.2020.269431
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发表时间：
2022-03-01
期刊：
影响因子：
10.1
通讯作者：
Hayashi Y
中科院分区：
文献类型：
--
作者：
Kaburagi T;Yamato G;Shiba N;Yoshida K;Hara Y;Tabuchi K;Shiraishi Y;Ohki K;Sotomatsu M;Arakawa H;Matsuo H;Shimada A;Taki T;Kiyokawa N;Tomizawa D;Horibe K;Miyano S;Taga T;Adachi S;Ogawa S;Hayashi Y
RAS通路的改变与多种血液恶性肿瘤的发病机制有关。然而，其在儿童急性髓细胞白血病（AML）的临床相关性还没有得到很好的表征。我们分析了328例儿童原发性AML患者RAS通路改变的频率、临床意义和预后相关性。328例患者中有80例（24.4%）检测到RAS通路改变：NF 1（n=7，2.1%）、PTPN 11（n=15，4.6%）、CBL（n=6，1.8%）、NRAS（n=44，13.4%）、KRAS（n=12，3.7%）。RAS通路中的大多数这些改变与信号转导通路的其他畸变如FLT 3-ITD（P=0.001）和KIT突变（P=0.004）也是相互排斥的。NF-1基因突变常见于复杂核型患者（P=0.031），多因素分析显示NF-1基因突变是总生存率（OS）差的独立预测因子（P=0.007）。至少有四个与NF 1改变的7例患者有双等位基因失活。在CBFB-MYH 11患者中经常观察到NRAS突变，并且在多变量分析中是有利结局的独立预测因素（OS，P=0.023;无事件生存期[EFS]，P=0.037）。PTPN 11突变的患者比无PTPN 11突变的患者更频繁地接受干细胞移植（P=0.035），并且显示出较差的EFS（P=0.013）。RAS通路改变的详细分析可能使儿科AML的预后分层更准确，并可能提供与该信号转导通路相关的新的治疗分子靶点。
RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) of 328 patients: NF1 (n=7, 2.1%), PTPN11 (n=15, 4.6%), CBL (n=6, 1.8%), NRAS (n=44, 13.4%), KRAS (n=12, 3.7%). Most of these alterations in the RAS pathway were mutually exclusive also together with other aberrations of signal transduction pathways such as FLT3-ITD (P=0.001) and KIT mutation (P=0.004). NF1 alterations were frequently detected in patients with complex karyotype (P=0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (P=0.007). At least four of seven patients with NF1 alterations had biallelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis (OS, P=0.023; event-free survival [EFS], P=0.037). Patients with PTPN11 mutations more frequently received stem cell transplantation (P=0.035) and showed poor EFS than patients without PTPN11 mutations (P=0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.
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影响因子：
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影响因子：
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