Targeting the wee1 kinase for treatment of pediatric Down syndrome acute myeloid leukemia

摘要: Background Most Down syndrome children with acute myeloid leukemia (DS-AML) have an overall excellent prognosis, however, patients who suffer induction failure or relapse, extremely poor prognosis. Hence, new therapies need to be developed for this subgroup of DS-AML patients. One therapeutic approach is preventing cell cycle checkpoint activation by inhibiting the upstream kinase wee1 first-in-class inhibitor MK-1775 in combination standard genotoxic agent cytarabine (AraC). Procedure Using clinically relevant lines CMK and CMY, as well ex vivo primary patient samples, ability enhance cytotoxicity AraC was investigated MTT assays. The mechanism which enhanced using Western blots probe CDK1 H2AX phosphorylation flow cytometry determine apoptosis, arrest, DNA damage, aberrant mitotic entry. Results MK-1775 alone had modest single-agent activity, able synergize causing proliferation arrest both AraC-induced apoptosis. decrease inhibitory CDK1(Y15) at relatively low concentration 100 nM after only 4 hours. Furthermore, it damage induced partially abrogate arrest. Importantly, enhancement appeared early S-phase. Conclusions MK-1775 cells presents a promising treatment DS-AML. Pediatr Blood Cancer 2014; 61:1767–1773. © 2014 Wiley Periodicals, Inc.