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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.