title: GPR84 sustains aberrant β-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis.
abstract: β-catenin is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). Targeted inhibition of β-catenin signaling has been hampered by the lack of pathway components amenable to pharmacologic manipulation. Here we identified a novel β-catenin regulator, GPR84, a member of the G protein-coupled receptor family that represents a highly tractable class of drug targets. High GPR84 expression levels were confirmed in human and mouse AML LSCs compared with hematopoietic stem cells (HSCs). Suppression of GPR84 significantly inhibited cell growth by inducing G1-phase cell-cycle arrest in pre-LSCs, reduced LSC frequency, and impaired reconstitution of stem cell-derived mixed-lineage leukemia (MLL) AML, which represents an aggressive and drug-resistant subtype of AML. The GPR84-deficient phenotype in established AML could be rescued by expression of constitutively active β-catenin. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a-transduced stem cells. Microarray analysis demonstrated that GPR84 significantly upregulated a small set of MLL-fusion targets and β-catenin coeffectors, and downregulated a hematopoietic cell-cycle inhibitor. Altogether, our data reveal a previously unrecognized role of GPR84 in maintaining fully developed AML by sustaining aberrant β-catenin signaling in LSCs, and suggest that targeting the oncogenic GPR84/β-catenin signaling axis may represent a novel therapeutic strategy for AML.
authors.affiliation: Cancer and Stem Cell Biology Group, Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia;
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Dietrich
authors.affiliation: Cancer and Stem Cell Biology Group, Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia;
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.affiliation: Cancer and Stem Cell Biology Group, Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia;
authors.forename: Halina H L
authors.initials: HH
authors.lastname: Leung
authors.affiliation: Cancer and Stem Cell Biology Group, Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia;
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Lynch
authors.affiliation: Cancer and Stem Cell Biology Group, Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia;
authors.forename: Estrella
authors.initials: E
authors.lastname: Gonzales
authors.affiliation: Kids Cancer Alliance, Translational Cancer Research Centre for Kids, Cancer Institute New South Wales, Sydney, NSW, Australia; Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia;
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia;
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia;
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.affiliation: Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY; and.
authors.forename: Jianlong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cancer and Stem Cell Biology Group, Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Jenny Yingzi
authors.identifier: http://orcid.org/0000-0002-1325-7943
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction / Q000235:genetics; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C431700:GPR84 protein, human; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D051176:beta Catenin