title: Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia.
abstract: Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedback regulation of Erk signaling. Studying negative feedback regulation of Erk in genetic experiments at three different levels, we found that Spry2, Dusp6, and Etv5 were essential for oncogenic transformation in mouse models for pre-B acute lymphoblastic leukemia (ALL). Interestingly, a small molecule inhibitor of DUSP6 selectively induced cell death in patient-derived pre-B ALL cells and overcame conventional mechanisms of drug-resistance.
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Seyedmehdi
authors.initials: S
authors.lastname: Shojaee
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Caeser
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Maike
authors.initials: M
authors.lastname: Buchner
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK.
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Srividya
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Hurtz
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Lai N
authors.initials: LN
authors.lastname: Chan
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Klemm
authors.affiliation: III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Heidelberg 68167, Germany.
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yi Hua
authors.initials: YH
authors.lastname: Qiu
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Nianxiang
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY 10466, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.affiliation: Howard Hughes Medical Institute and Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH 45247, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Molkentin
authors.affiliation: Division of Hematology and Oncology, Cedars Sinai Medical Center, Los Angeles, CA 90095, USA; Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.affiliation: Department of Pathology, University of New Mexico Cancer Center, Albuquerque, NM 87102, USA.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: markus.muschen@ucsf.edu.
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D051863:Host Cell Factor C1; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases; D054852:Small Molecule Libraries / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C513242:Etv5 protein, mouse; D051863:Host Cell Factor C1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D054852:Small Molecule Libraries; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse