ASPP1 (PPP1R13B) belongs to a family of p53-binding proteins and enhances apoptosis by stimulation of p53-transactivation of selected proapoptotic target genes. It is preferentially expressed in hematopoietic stem cells (HSC) and together with p53 preserves the genomic integrity of the HSC pool. Consequently, dysfunction of ASPP1 has been associated with malignant transformation and development of acute lymphoblastic leukemias and lymphomas - whereas methylation of the promoter region is linked to reduced transcription and ultimately attenuated expression of ASPP1. The role of ASPP1 in AML is not known. We now show that impaired regulation of PPP1R13B contributes to the biology of leukemogenesis and primary therapy resistance in AML. PPP1R13B mRNA expression patterns thereby define a distinct prognostic profile - which is not reflected by the European leukemia net (ELN) risk score. These findings have direct therapeutic implications and we provide a strategy to restore ASPP1 protein levels using hypomethylating agents to sensitize cells towards proapoptotic drugs. Prospective clinical trials are warranted to investigate the role of ASPP1 (PPP1R13B) as a biomarker for risk stratification and as a potential therapeutic target to restore susceptibility to chemotherapy.

ASPP1 ( PPP1R13B ) 属于 p53 结合蛋白家族，通过刺激选定的促凋亡靶基因的 p53 反式激活来增强细胞凋亡。它优先在造血干细胞 (HSC) 中表达，并与 p53 一起保留 HSC 库的基因组完整性。因此，ASPP1 的功能障碍与急性淋巴细胞白血病和淋巴瘤的恶性转化和发展有关，而启动子区域的甲基化则与 ASPP1 的转录减少并最终减弱表达有关。 ASPP1 在 AML 中的作用尚不清楚。我们现在表明， PPP1R13B的调节受损有助于 AML 中白血病发生的生物学和主要治疗耐药性。因此， PPP1R13B mRNA 表达模式定义了独特的预后特征，而欧洲白血病网 (ELN) 风险评分并未反映出这一点。这些发现具有直接的治疗意义，我们提供了一种策略，使用低甲基化剂恢复 ASPP1 蛋白水平，使细胞对促凋亡药物敏感。有必要进行前瞻性临床试验来研究 ASPP1 (PPP1R13B)作为风险分层生物标志物和作为恢复化疗敏感性的潜在治疗靶点的作用。