title: Inhibition of WNT signaling in the bone marrow niche prevents the development of MDS in theApcdel/+MDS mouse model.
abstract: There is accumulating evidence that functional alteration(s) of the bone marrow (BM) microenvironment contribute to the development of some myeloid disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition to a cell-intrinsic role of WNT activation in leukemia stem cells, WNT activation in the BM niche is also thought to contribute to the pathogenesis of MDS and AML. We previously showed that theApc-haploinsufficient mice (Apcdel/+) model MDS induced by an aberrant BM microenvironment. We sought to determine whether Apc, a multifunctional protein and key negative regulator of the canonical β-catenin (Ctnnb1)/WNT-signaling pathway, mediates this disease through modulating WNT signaling, and whether inhibition of WNT signaling prevents the development of MDS inApcdel/+mice. Here, we demonstrate that loss of 1 copy ofCtnnb1is sufficient to prevent the development of MDS inApcdel/+mice and that altered canonical WNT signaling in the microenvironment is responsible for the disease. Furthermore, the US Food and Drug Administration (FDA)-approved drug pyrvinium delays and/or inhibits disease inApcdel/+mice, even when it is administered after the presentation of anemia. Other groups have observed increased nuclear CTNNB1 in stromal cells from a high frequency of MDS/AML patients, a finding that together with our results highlights a potential new strategy for treating some myeloid disorders.
authors.affiliation: Department of Medicine and.
authors.forename: Angela
authors.identifier: 0000-0001-9776-2228
authors.initials: A
authors.lastname: Stoddart
authors.affiliation: Department of Medicine and.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicine and.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Medicine and.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Fernald
authors.affiliation: Department of Medicine and.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Davis
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL; and.|University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL.
authors.forename: Jason X
authors.identifier: 0000-0001-7252-7221
authors.initials: JX
authors.lastname: Cheng
authors.affiliation: Department of Medicine and.|University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL.
authors.forename: Michelle M
authors.identifier: 0000-0002-8749-2655
authors.initials: MM
authors.lastname: Le Beau
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D017491:Genes, APC; D057895:Haploinsufficiency; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D011774:Pyrvinium Compounds / Q000494:pharmacology; D055153:Stem Cell Niche / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C495267:CTNNB1 protein, mouse; D011774:Pyrvinium Compounds; D051176:beta Catenin; C024631:pyrvinium