title: Tetraspanin 3 Is Required for the Development and Propagation of Acute Myelogenous Leukemia.
abstract: Acute Myelogenous Leukemia (AML) is an aggressive cancer that strikes both adults and children and is frequently resistant to therapy. Thus, identifying signals needed for AML propagation is a critical step toward developing new approaches for treating this disease. Here, we show that Tetraspanin 3 is a target of the RNA binding protein Musashi 2, which plays a key role in AML. We generated Tspan3 knockout mice that were born without overt defects. However, Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in mouse models of AML. Additionally, Tspan3 inhibition blocked growth of AML patient samples, suggesting that Tspan3 is also important in human disease. As part of the mechanism, we show that Tspan3 deficiency disabled responses to CXCL12/SDF-1 and led to defects in AML localization within the niche. These identify Tspan3 as an important regulator of aggressive leukemias and highlight a role for Tspan3 in oncogenesis.
authors.affiliation: Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.|Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Asan-si, Chungcheongnamdo 336-745, South Korea.
authors.forename: Hyog Young
authors.initials: HY
authors.lastname: Kwon
authors.affiliation: Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
authors.forename: Jeevisha
authors.initials: J
authors.lastname: Bajaj
authors.affiliation: Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Blevins
authors.affiliation: Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Konuma
authors.affiliation: Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
authors.forename: Joi
authors.initials: J
authors.lastname: Weeks
authors.affiliation: Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
authors.forename: Nikki K
authors.initials: NK
authors.lastname: Lytle
authors.affiliation: Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Koechlein
authors.affiliation: Division of Cell Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rizzieri
authors.affiliation: Department of Haematology, Singapore General Hospital, Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857.
authors.forename: Charles
authors.initials: C
authors.lastname: Chuah
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, WA 98109, USA.
authors.forename: Vivian G
authors.initials: VG
authors.lastname: Oehler
authors.affiliation: Center for Computational Biology and Bioinformatics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Sasik
authors.affiliation: Computational Science Research Center and Biomedical Informatics Research Center, San Diego State University, San Diego, CA 92182, USA.|Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Hardiman
authors.affiliation: Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093, USA.|Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Tannishtha
authors.initials: T
authors.lastname: Reya
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D016678:Genome; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D059470:Tetraspanins / Q000172:deficiency / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D054377:Chemokine CXCL12; D059470:Tetraspanins; C000607920:Tspan3 protein, human; C426223:Tspan3 protein, mouse; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse