Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease characterized by uncontrolled proliferation of hematopoietic precursor cells [1]. KMT2A (MLL) rearrangements are among the most frequent chromosomal abnormalities in AML [2]. The proportion of KMT2A rearrangements is higher in infants/children with AML [3]. KMT2A-rearranged (KMT2A-r) AML is also heterogeneous, with >60 different fusion partner genes identified [4]. The prognosis of patients with KMT2A-r AML varies based on the KMT2A fusion pattern [5]. Therefore, some fusion patterns are currently used for risk stratification of AML treatment [6]. In KMT2A-r AML, RAS pathway genes are frequently mutated [7, 8]. Our recent study identified mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene as adverse prognostic factors in KMT2A-r AML [9]. However, the effect of the location of KRAS mutations on prognosis remains unclear because of the small sample size.

In this study, targeted sequencing was performed in samples from patients enrolled in the Japan Children’s Cancer Group (JCCG) AML-99/AML-05/AML-12 studies, which was analyzed using the data in the TARGET-AML cohort [3]. Then, we examined the prognostic significance of KRAS mutations based on their location in patients with KMT2A-r AML (n = 225) and non-KMT2A-r AML (n = 882). For further information on patients and study protocol, DNA sequencing and mutation calling, and statistical analysis, please refer to Supplemental Methods. This study was conducted following the principles defined in the Declaration of Helsinki and approved by the ethics committees of all participating institutions, the Kyoto University Medical Ethics Committee, and the JCCG Research Review Committee (approval numbers: G0361 and 106). All patients, or their parents or guardians, provided written informed consent.

急性髓系白血病(AML)是一种遗传和临床异质性疾病，其特征是造血前体细胞增殖失控[1]。KMT2A ( MLL ) 重排是 AML 中最常见的染色体异常之一 [2]。患有 AML 的婴儿/儿童中KMT2A 重排的比例较高 [3]。KMT2A重排 ( KMT2A -r) AML 也是异质性的，已识别出超过 60 个不同的融合伴侣基因 [4]。KMT2A -r AML患者的预后因KMT2A融合模式而异 [5]。因此，目前一些融合模式被用于AML治疗的风险分层[6]。在KMT2A -r AML 中，RAS 通路基因经常发生突变 [7, 8]。我们最近的研究发现 Kirsten 大鼠肉瘤病毒癌基因同源物 ( KRAS ) 基因的突变是KMT2A -r AML的不良预后因素[9]。然而，由于样本量较小，KRAS突变的位置对预后的影响仍不清楚。

在这项研究中，对参加日本儿童癌症小组 (JCCG) AML-99/AML-05/AML-12 研究的患者样本进行了靶向测序，并使用 TARGET-AML 队列中的数据进行了分析 [3] 。然后，我们根据KRAS突变在KMT2A -r AML ( n  = 225) 和非KMT2A -r AML ( n  = 882)患者中的位置检查了其预后意义。有关患者和研究方案、DNA 测序和突变识别以及统计分析的更多信息，请参阅补充方法。本研究遵循赫尔辛基宣言中规定的原则进行，并得到所有参与机构的伦理委员会、京都大学医学伦理委员会和 JCCG 研究审查委员会的批准（批准号：G0361 和 106）。所有患者或其父母或监护人均提供了书面知情同意书。