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Cancer Res. 2017 Aug 1;77(15):4116-4126. doi: 10.1158/0008-5472.CAN-17-0202. Epub 2017 Jun 13.

β-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q).

Author information

1
Department of Medicine, Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, Illinois.
2
Fudan University Zhong Shan Hospital, Shanghai, China.
3
College of Arts and Sciences, Shanghai New York University, Shanghai, China.
4
Department of Pediatrics, Division of Pediatric Hematology Oncology, University of Illinois at Chicago (Fellow, UIC-Rush-Stroger Fellowship Program, Chicago), Chicago, Illinois.
5
Department of Laboratory Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan.
6
Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
7
Department of Medicine, Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, Illinois. zjqian@uic.edu.

Abstract

Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with de novo myelodysplastic syndromes (MDS) and therapy-related MDS or acute myeloid leukemia (t-MDS/tAML). Emerging evidence indicates that activation of the Wnt/β-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether β-catenin is a potential therapeutic target for myeloid neoplasms with del(5q) has yet to be evaluated. Here, we report that genetic deletion of a single allele of β-catenin rescues ineffective hematopoiesis in an Apc haploinsufficient mouse model, which recapitulates several characteristic features of the preleukemic stage of myeloid neoplasms with a -5/del(5q). In addition, loss of a single allele of β-catenin reversed the defective self-renewal capacity of Apc-haploinsufficient hematopoietic stem cells and reduced the frequency of apoptosis induced by Apc haploinsufficiency. Suppression of β-catenin by indomethacin or β-catenin shRNA reduced proliferation and survival of human leukemia cell lines with del(5q) but not of control leukemia cell lines in vitro; β-catenin inactivation also inhibited leukemia progression in vivo in xenograft mice reconstituted with del(5q) leukemia cell lines. Inhibition of β-catenin also stunted growth and colony-forming abilities of primary bone marrow cells from del(5q) AML patients in vitro Overall, our data support the idea that β-catenin could serve as a therapeutic target for the treatment of myeloid neoplasms with del(5q). Cancer Res; 77(15); 4116-26. ©2017 AACR.

PMID:
28611040
PMCID:
PMC5559383
DOI:
10.1158/0008-5472.CAN-17-0202
[Indexed for MEDLINE]
Free PMC Article

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