■TP53突变与急性髓细胞性白血病(AML)和高危骨髓增生异常综合征(HR-MDS)的不良预后相关。然而,整合的遗传,表观遗传,TP53突变的AML/HR-MDS的免疫学前景尚不明确。
■要定义遗传,表观遗传,TP53突变型和TP53野生型AML和HR-MDS患者的免疫学景观。
■在阿扎胞苷±抗PD-L1抗体durvalumab的随机FUSION试验中治疗的TP53突变和TP53野生型患者的事后分析。
■我们进行了广泛的分子,表观遗传,以及在61例TP53突变疾病患者的完整注释临床试验数据集上的免疫测定(37例AML,24MDS)和144TP53野生型(89AML,55例MDS)患者,所有患者均接受了基于阿扎胞苷的治疗.进行来自筛选骨髓(BM)的38个基因靶向的骨髓突变分析。DNA甲基化阵列,通过流式细胞术进行免疫表型和免疫检查点表达,和通过批量RNA测序的基因表达谱在基线和试验期间进行评估.
■来自外周血的全局DNA甲基化独立于TP53突变和等位基因状态。AZA治疗导致独立于TP53突变状态的全局DNA甲基化评分的统计学显著降低。在TP53突变患者的BM中,我们发现,与TP53野生型相比,PD-L1等抑制性免疫检查点蛋白具有更高的T细胞数量和上调.RNA测序分析显示,TP53突变体样品中髓样免疫检查点基因LILRB3的表达更高,这表明了一种新的治疗靶标。
■这种遗传的综合分析,表观遗传,和TP53突变型AML/HR-MDS的免疫表型景观表明,导致免疫抑制微环境的免疫景观差异而非表观遗传差异导致TP53突变型AML/HR-MDS具有单-或多命中TP53突变状态的不良预后。
■融合试验(NCT02775903)。
UNASSIGNED: TP53 mutations are associated with an adverse prognosis in acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (HR-MDS). However, the integrated genetic, epigenetic, and immunologic landscape of TP53-mutated AML/HR-MDS is not well defined.
UNASSIGNED: To define the genetic, epigenetic, and immunologic landscape of TP53-mutant and TP53 wild-type AML and HR-MDS patients.
UNASSIGNED: Post hoc analysis of TP53-mutant and TP53 wild-type patients treated on the randomized FUSION trial with azacitidine ± the anti-PD-L1 antibody durvalumab.
UNASSIGNED: We performed extensive molecular, epigenetic, and immunologic assays on a well-annotated clinical trial dataset of 61 patients with TP53-mutated disease (37 AML, 24 MDS) and 144 TP53 wild-type (89 AML, 55 MDS) patients, all of whom received azacitidine-based therapy. A 38 gene-targeted myeloid mutation analysis from screening bone marrow (BM) was performed. DNA methylation arrays, immunophenotyping and immune checkpoint expression by flow cytometry, and gene expression profiles by bulk RNA sequencing were assessed at baseline and serially during the trial.
UNASSIGNED: Global DNA methylation from peripheral blood was independent of TP53 mutation and allelic status. AZA therapy led to a statistically significant decrease in global DNA methylation scores independent of TP53 mutation status. In BM from TP53-mutant patients, we found both a higher T-cell population and upregulation of inhibitory immune checkpoint proteins such as PD-L1 compared to TP53 wild-type. RNA sequencing analyses revealed higher expression of the myeloid immune checkpoint gene LILRB3 in TP53-mutant samples suggesting a novel therapeutic target.
UNASSIGNED: This integrated analysis of the genetic, epigenetic, and immunophenotypic landscape of TP53 mutant AML/HR-MDS suggests that differences in the immune landscape resulting in an immunosuppressive microenvironment rather than epigenetic differences contribute to the poor prognosis of TP53-mutant AML/HR-MDS with mono- or multihit TP53 mutation status.
UNASSIGNED: FUSION trial (NCT02775903).