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 pre-leukemic 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 (HSC) 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).
• Apc regulates the function of HSCs/HPCs largely through a b-catenin-mediated pathway.• Multiple downstream targets of Apc may be involved in the regulation of HSC self-renewal. . In assays of long-term stem cell function, the HSCs with deficiency of both Apc and b-catenin displayed a significantly enhanced self-renewal capacity compared with b-catenin-deficient and control HSCs. Our findings suggest that Apc regulates the survival, proliferation, and differentiation of HSCs/HPCs largely through a b-catenin-mediated pathway. They also indicate that multiple downstream targets of Apc including b-catenin may coordinately regulate HSC self-renewal. (Blood. 2013;121(20):4063-4072)
<p>Supplemental Figure 1. Indo suppresses beta-catenin expression. (A) Luciferase reporter assay of beta-catenin transcription activity. (B) beta-catenin expression in MDSL and UoC-M1 cells after Indo treatment for 72 hours. *, P <0.05. Supplemental Figure 2. Indo induces apoptosis of human MDSL, UoCM1 and KG1 cell lines with a del(5q). The histograms of the flow cytometric analysis of apoptosis of leukemia cell lines treated with 100μM Indo. Supplemental Figure 3. beta-catenin suppression induces apoptosis of human MDSL, UoCM1 and KG1 cell lines with a del(5q). The histograms of the flow cytometric analysis of apoptosis of leukemia cell lines expressing PLKO or PLKO-beta-catenin shRNAs.</p>
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