title: MEIS1-mediated transactivation of synaptotagmin-like 1 promotes CXCL12/CXCR4 signaling and leukemogenesis.
abstract: The TALE-class homeoprotein MEIS1 specifically collaborates with HOXA9 to drive myeloid leukemogenesis. Although MEIS1 alone has only a moderate effect on cell proliferation in vitro, it is essential for the development of HOXA9-induced leukemia in vivo. Here, using murine models of leukemogenesis, we have shown that MEIS1 promotes leukemic cell homing and engraftment in bone marrow and enhances cell-cell interactions and cytokine-mediated cell migration. We analyzed global DNA binding of MEIS1 in leukemic cells as well as gene expression alterations in MEIS1-deficent cells and identified synaptotagmin-like 1 (Sytl1, also known as Slp1) as the MEIS1 target gene that cooperates with Hoxa9 in leukemogenesis. Replacement of SYTL1 in MEIS1-deficent cells restored both cell migration and engraftment. Further analysis revealed that SYTL1 promotes cell migration via activation of the CXCL12/CXCR4 axis, as SYTL1 determines intracellular trafficking of CXCR4. Together, our results reveal that MEIS1, through induction of SYTL1, promotes leukemogenesis and supports leukemic cell homing and engraftment, facilitating interactions between leukemic cells and bone marrow stroma.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Mayuka
authors.initials: M
authors.lastname: Nakatake
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuwata
authors.forename: Arnaud
authors.initials: A
authors.lastname: Couzinet
authors.forename: Ryo
authors.initials: R
authors.lastname: Goitsuka
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology / Q000473:pathology; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D008565:Membrane Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4; C431146:SYTL1 protein, human; D033921:Vesicular Transport Proteins