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

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/?-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether ?-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 ?-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 ?-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 ?-catenin by indomethacin or ?-catenin shRNA reduced proliferation and survival of human leukemia cell lines with del(5q) but not of control leukemia cell lines in vitro; ?-catenin inactivation also inhibited leukemia progression in vivo in xenograft mice reconstituted with del(5q) leukemia cell lines. Inhibition of ?-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 ?-catenin could serve as a therapeutic target for the treatment of myeloid neoplasms with del(5q). Cancer Res; 77(15); 4116-26. ©2017 AACR.

SUBMITTER: Li L 

PROVIDER: S-EPMC5559383 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature