title: AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/β-catenin signaling pathway.
abstract: Developing novel therapies that suppress self-renewal of leukemia stem cells may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase (COX)-2 and β-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. Inhibition of COX suppresses β-catenin activation and serial replating of AE(+) mouse HSPCs. Genetic knockdown of β-catenin also abrogates the clonogenic growth of AE(+) mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/β-catenin-dependent signaling pathway in tumor initiation, growth, and self-renewal, and in providing the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments.
authors: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors: Yiyun
authors: Y
authors: Zhang
authors: Jianfeng
authors: J
authors: Wang
authors: Justin
authors: J
authors: Wheat
authors: Xi
authors: X
authors: Chen
authors: Shan
authors: S
authors: Jin
authors: Hossein
authors: H
authors: Sadrzadeh
authors: Amir T
authors: AT
authors: Fathi
authors: Randall T
authors: RT
authors: Peterson
authors: Andrew L
authors: AL
authors: Kung
authors: David A
authors: DA
authors: Sweetser
authors: Jing-Ruey Joanna
authors: JR
authors: Yeh
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D000075142:RUNX1 Translocation Partner 1 Protein; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014183:Transplantation, Heterologous; D015027:Zebrafish; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D016861:Cyclooxygenase Inhibitors; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D013449:Sulfonamides; D051176:beta Catenin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C012655:nimesulide
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