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Abstract：
Incidence, molecular presentation and outcome of acute myeloid leukaemia (AML) are influenced by sex, but little attention has been directed at untangling sex-related molecular and phenotypic differences between female and male patients. While increased incidence and poor risk are generally associated with a male phenotype, the poor prognostic FLT3 internal tandem duplication (FLT3-ITD) mutation and co-mutations with NPM1 and DNMT3A are overrepresented in female AML. Here, we have investigated the relationship between sex and FLT3-ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity in four cohorts: Beat AML, LAML-TCGA and two independent HOVON/SAKK cohorts, comprising 1755 AML patients in total. We found prevalent sex-associated molecular differences. Co-occurrence of FLT3-ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3-ITDs were characterized by additional mutations in RNA splicing and epigenetic modifier genes. We observed diverging expression of multiple leukaemia-associated genes as well as discrepant ex vivo drug responses, suggestive of discrete functional properties. Importantly, significant prognostication was observed only in female FLT3-ITD-mutated AML. Thus, we suggest optimization of FLT3-ITD mutation status as a clinical tool in a sex-adjusted manner and hypothesize that prognostication, prediction and development of therapeutic strategies in AML could be improved by including sex-specific considerations.
摘要：
发病率,急性髓系白血病（AML）的分子表现和结果受性别影响，但很少有人关注女性和男性患者之间与性别相关的分子和表型差异。虽然发病率增加和低风险通常与男性表型有关，FLT3内部串联重复(FLT3-ITD)突变和NPM1和DNMT3A的共突变在女性AML中的预后较差.这里,我们通过比较临床数据来研究性别与FLT3-ITD突变状态之间的关系，突变谱,四个队列的基因表达和离体药物敏感性：BeatAML，LAML-TCGA和两个独立的HOVON/SAKK队列，包括总共1755名AML患者。我们发现普遍存在的性别相关分子差异。FLT3-ITD共现,NPM1和DNMT3A突变在女性中代表过多，而FLT3-ITDs男性的特征在于RNA剪接和表观遗传修饰基因的额外突变。我们观察到多个白血病相关基因的不同表达以及不同的离体药物反应，暗示离散的功能特性。重要的是,仅在女性FLT3-ITD突变的AML中观察到显著的预后.因此，我们建议以性别调整的方式优化FLT3-ITD突变状态作为临床工具，并假设预后，通过纳入性别特异性考虑因素,可以改善AML治疗策略的预测和发展.
