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Targeting the wee1 kinase for treatment of pediatric Down syndrome acute myeloid leukemia
Author(s) -
Caldwell J. Timothy,
Edwards Holly,
Buck Steven A.,
Ge Yubin,
Taub Jeffrey W.
Publication year - 2014
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.25081
Subject(s) - cytarabine , cyclin dependent kinase 1 , myeloid leukemia , cell cycle , wee1 , cell cycle checkpoint , cancer research , medicine , cytotoxicity , apoptosis , flow cytometry , dna damage , immunology , biology , in vitro , dna , cancer , genetics
Background Most Down syndrome children with acute myeloid leukemia (DS‐AML) have an overall excellent prognosis, however, patients who suffer an induction failure or relapse, have an extremely poor prognosis. Hence, new therapies need to be developed for this subgroup of DS‐AML patients. One new therapeutic approach is preventing cell cycle checkpoint activation by inhibiting the upstream kinase wee1 with the first‐in‐class inhibitor MK‐1775 in combination with the standard genotoxic agent cytarabine (AraC). Procedure Using the clinically relevant DS‐AML cell lines CMK and CMY, as well as ex vivo primary DS‐AML patient samples, the ability of MK‐1775 to enhance the cytotoxicity of AraC was investigated with MTT assays. The mechanism by which MK‐1775 enhanced AraC cytotoxicity was investigated in the cell lines using Western blots to probe CDK1 and H2AX phosphorylation and flow cytometry to determine apoptosis, cell cycle arrest, DNA damage, and aberrant mitotic entry. Results MK‐1775 alone had modest single‐agent activity, however, MK‐1775 was able to synergize with AraC in causing proliferation arrest in both cell lines and primary patient samples, and enhance AraC‐induced apoptosis. MK‐1775 was able to decrease inhibitory CDK1(Y15) phosphorylation at the relatively low concentration of 100 nM after only 4 hours. Furthermore, it was able to enhance DNA damage induced by AraC and partially abrogate cell cycle arrest. Importantly, the DNA damage enhancement appeared in early S‐phase. Conclusions MK‐1775 is able to enhance the cytotoxicity of AraC in DS‐AML cells and presents a promising new treatment approach for DS‐AML. Pediatr Blood Cancer 2014; 61:1767–1773. © 2014 Wiley Periodicals, Inc.