The chronic lymphocytic leukemia (CLL) armamentarium has evolved significantly, with novel therapies that inhibit Bruton Tyrosine Kinase, PI3K delta and/or the BCL2 protein improving outcomes. Still, the clinical course of CLL patients is highly variable and most previously recognized prognostic features lack the capacity to predict response to modern treatments indicating the need for new prognostic markers. In this study, we identified four epigenetically distinct proteomic signatures of a large cohort of CLL and related diseases derived samples (n = 871) using reverse phase protein array technology. These signatures are associated with clinical features including age, cytogenetic abnormalities [trisomy 12, del(13q) and del(17p)], immunoglobulin heavy-chain locus (IGHV) mutational load, ZAP-70 status, Binet and Rai staging as well as with the outcome measures of time to treatment and overall survival. Protein signature membership was identified as predictive marker for overall survival regardless of other clinical features. Among the analyzed epigenetic proteins, EZH2, HDAC6, and loss of H3K27me3 levels were the most independently associated with poor survival. These findings demonstrate that proteomic based epigenetic biomarkers can be used to better classify CLL patients and provide therapeutic guidance.

慢性淋巴细胞白血病 (CLL) 医疗设备已取得显着进展，新疗法可抑制布鲁顿酪氨酸激酶、PI3K delta 和/或 BCL2 蛋白，从而改善结果。尽管如此，CLL 患者的临床过程是高度可变的，并且大多数先前公认的预后特征缺乏预测对现代治疗反应的能力，这表明需要新的预后标志物。在这项研究中，我们确定了一大群 CLL 和相关疾病衍生样本的四种表观遗传学上不同的蛋白质组学特征（n = 871) 使用反相蛋白质阵列技术。这些特征与临床特征相关，包括年龄、细胞遗传学异常 [12 三体、del(13q) 和 del(17p)]、免疫球蛋白重链基因座 (IGHV) 突变负荷、ZAP-70 状态、Binet 和 Rai 分期以及与治疗时间和总生存期的结果措施。无论其他临床特征如何，蛋白质特征成员都被确定为总体存活率的预测标志物。在分析的表观遗传蛋白中，EZH2、HDAC6 和 H3K27me3 水平的缺失与存活率差最独立相关。这些发现表明，基于蛋白质组学的表观遗传生物标志物可用于更好地对 CLL 患者进行分类并提供治疗指导。