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

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

Apc regulates the function of hematopoietic stem cells largely through ß-catenin-dependent mechanisms.

Emerging evidence suggests that adenomatous polyposis coli (Apc) plays a critical role in the maintenance of hematopoietic stem/progenitor cells (HSCs/HPCs). The molecular pathways responsible for the function of Apc in HSCs/HPCs remain unclear. By genetic approach, we demonstrated that inactivation of ß-catenin rescued the exhaustion of Apc-deficient HSCs/HPCs, thereby preventing bone marrow failure in Apc-deficient mice. ß-catenin loss inhibited the excessive proliferation and apoptosis of Apc-deficient HSCs/HPCs, as well as their defects in myeloid and erythroid differentiation. In addition, loss of ß-catenin reversed the down-regulation of Cdkn1a, Cdkn1b, and Mcl1 induced by Apc ablation in Lin(-)Sca(+)c-Kit(+). In assays of long-term stem cell function, the HSCs with deficiency of both Apc and ß-catenin displayed a significantly enhanced self-renewal capacity compared with ß-catenin-deficient and control HSCs. Our findings suggest that Apc regulates the survival, proliferation, and differentiation of HSCs/HPCs largely through a ß-catenin-mediated pathway. They also indicate that multiple downstream targets of Apc including ß-catenin may coordinately regulate HSC self-renewal.