Targeting the Wee1 Kinase for Treatment of Pediatric Down Syndrome Acute Myeloid Leukemia

Overview

Journal Pediatr Blood Cancer

Specialties Hematology
Oncology
Pediatrics

Date 2014 Jun 26

PMID 24962331

Citations 16

Authors

J Timothy Caldwell

Holly Edwards

Steven A Buck

Yubin Ge

Jeffrey W Taub

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Down syndrome-associated leukaemias: current evidence and challenges.

Mason N, Cahill H, Diamond Y, McCleary K, Kotecha R, Marshall G Ther Adv Hematol. 2024; 15:20406207241257901.

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Clinical and biological aspects of myeloid leukemia in Down syndrome.

Boucher A, Caldwell K, Crispino J, Flerlage J Leukemia. 2021; 35(12):3352-3360.

PMID: 34518645 PMC: 8639661. DOI: 10.1038/s41375-021-01414-y.

RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis.

Carr R, Vorobyev D, Lasho T, Marks D, Tolosa E, Vedder A Nat Commun. 2021; 12(1):2901.

PMID: 34006870 PMC: 8131698. DOI: 10.1038/s41467-021-23186-w.

A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target.

Luserna di Rora A, Cerchione C, Martinelli G, Simonetti G J Hematol Oncol. 2020; 13(1):126.

PMID: 32958072 PMC: 7507691. DOI: 10.1186/s13045-020-00959-2.

SETD2 mutations confer chemoresistance in acute myeloid leukemia partly through altered cell cycle checkpoints.

Dong Y, Zhao X, Feng X, Zhou Y, Yan X, Zhang Y Leukemia. 2019; 33(11):2585-2598.

PMID: 30967619 PMC: 6785365. DOI: 10.1038/s41375-019-0456-2.

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