A Novel Combination of Decitabine and Etoposide Greatly Improves the Survival of TP53 Mutation AML/MDS Patients by Targeting Notch1 Signaling Pathway

There is still a lack of effective treatments for elderly AML/MDS patients, especially those with TP53 mutation. We conducted a prospective, multicenter clinical trial to evaluate decitabine and etoposide based regimen in elderly AML/MDS patients and found the median OS of TP53 mutation AML/MDS was improved to 31 months. Moreover, the administration of decitabine and etoposide greatly reduced TP53 mutant AML tumor burden in NSG mice model. Decitabine and etoposide induced significant apoptosis and differentiation of TP53 mutant myeloid tumor cells in vitro. RNA sequencing data and CRISPR-Cas9 gene editing indicated that drug-induced apoptosis and differentiation, were predominantly dependent on Notch1 signaling pathway. We also found that normal p53 function could inhibit Notch1 activation, whereas decitabine and etoposide could activate Notch1 in dysfunctional TP53 mutant AML/MDS. These findings indicate that treatment of elderly AML/MDS patients may need to be developed into a more precise, personalized chemotherapy in the future.