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

Abstract

<div>Abstract<p>Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with <i>de novo</i> 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 <i>Apc</i> 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 <i>in vitro</i>; β-catenin inactivation also inhibited leukemia progression <i>in vivo</i> 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 <i>in vitro</i>. Overall, our data support the idea that β-catenin could serve as a therapeutic target for the treatment of myeloid neoplasms with del(5q). <i>Cancer Res; 77(15); 4116–26. ©2017 AACR</i>.</p></div>