title: Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia.
abstract: Despite recent advances in the cure rate of acute lymphoblastic leukaemia (ALL), the prognosis for patients with relapsed ALL remains poor. Here we identify FOXM1 as a candidate responsible for an aggressive clinical course. We show that FOXM1 levels peak at the pre-B-cell receptor checkpoint but are dispensable for normal B-cell development. Compared with normal B-cell populations, FOXM1 levels are 2- to 60-fold higher in ALL cells and are predictive of poor outcome in ALL patients. FOXM1 is negatively regulated by FOXO3A, supports cell survival, drug resistance, colony formation and proliferation in vitro, and promotes leukemogenesis in vivo. Two complementary approaches of pharmacological FOXM1 inhibition-(i) FOXM1 transcriptional inactivation using the thiazole antibiotic thiostrepton and (ii) an FOXM1 inhibiting ARF-derived peptide-recapitulate the findings of genetic FOXM1 deletion. Taken together, our data identify FOXM1 as a novel therapeutic target, and demonstrate feasibility of FOXM1 inhibition in ALL.
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Maike
authors.initials: M
authors.lastname: Buchner
authors.affiliation: 1] Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA [2] Department of Haematology, University of Cambridge, Cambridge CB2 OAH, UK.
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Klemm
authors.affiliation: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hem/Onc Division, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Flach
authors.affiliation: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hem/Onc Division, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Hilde
authors.identifier: 0000000192873375
authors.initials: H
authors.lastname: Schjerven
authors.affiliation: Division of Hematology and Oncology, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10466, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
authors.forename: Dragana
authors.initials: D
authors.lastname: Kopanja
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
authors.forename: Pradip
authors.initials: P
authors.lastname: Raychaudhuri
authors.affiliation: 1] Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA [2] Department of Haematology, University of Cambridge, Cambridge CB2 OAH, UK.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002986:Clinical Trials as Topic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000072278:Forkhead Box Protein M1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051379:Mice; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D015398:Signal Transduction; D016019:Survival Analysis; D013883:Thiostrepton / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; C107585:FOXM1 protein, human; C499517:FOXO3 protein, human; D000072278:Forkhead Box Protein M1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D010455:Peptides; D013883:Thiostrepton