Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia
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 r...
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| Vydáno v: | Cancer cell Ročník 28; číslo 1; s. 114 - 128 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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13.07.2015
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| ISSN: | 1878-3686 |
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| 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. |
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| AbstractList | 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. 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. |
| Author | Qiu, Yi Hua Molkentin, Jeffery Hofmann, Wolf-Karsten Willman, Cheryl L Caeser, Rebecca Müschen, Markus Swaminathan, Srividya Zhang, Nianxiang Koeffler, H Phillip Hurtz, Christian Melnick, Ari Buchner, Maike Geng, Huimin Klemm, Lars Chan, Lai N Park, Eugene Kornblau, Steven M Coombes, Kevin R Hunger, Stephen P Paietta, Elisabeth Shojaee, Seyedmehdi |
| Author_xml | – sequence: 1 givenname: Seyedmehdi surname: Shojaee fullname: Shojaee, Seyedmehdi organization: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA – sequence: 2 givenname: Rebecca surname: Caeser fullname: Caeser, Rebecca organization: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK – sequence: 3 givenname: Maike surname: Buchner fullname: Buchner, Maike organization: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA – sequence: 4 givenname: Eugene surname: Park fullname: Park, Eugene organization: Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK – sequence: 5 givenname: Srividya surname: Swaminathan fullname: Swaminathan, Srividya organization: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA – sequence: 6 givenname: Christian surname: Hurtz fullname: Hurtz, Christian organization: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA – sequence: 7 givenname: Huimin surname: Geng fullname: Geng, Huimin organization: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA – sequence: 8 givenname: Lai N surname: Chan fullname: Chan, Lai N organization: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA – sequence: 9 givenname: Lars surname: Klemm fullname: Klemm, Lars organization: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA – sequence: 10 givenname: Wolf-Karsten surname: Hofmann fullname: Hofmann, Wolf-Karsten organization: III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Heidelberg 68167, Germany – sequence: 11 givenname: Yi Hua surname: Qiu fullname: Qiu, Yi Hua organization: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA – sequence: 12 givenname: Nianxiang surname: Zhang fullname: Zhang, Nianxiang organization: Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA – sequence: 13 givenname: Kevin R surname: Coombes fullname: Coombes, Kevin R organization: Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA – sequence: 14 givenname: Elisabeth surname: Paietta fullname: Paietta, Elisabeth organization: Albert Einstein College of Medicine, Bronx, NY 10466, USA – sequence: 15 givenname: Jeffery surname: Molkentin fullname: Molkentin, Jeffery organization: Howard Hughes Medical Institute and Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH 45247, USA – sequence: 16 givenname: H Phillip surname: Koeffler fullname: Koeffler, H Phillip organization: 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 – sequence: 17 givenname: Cheryl L surname: Willman fullname: Willman, Cheryl L organization: Department of Pathology, University of New Mexico Cancer Center, Albuquerque, NM 87102, USA – sequence: 18 givenname: Stephen P surname: Hunger fullname: Hunger, Stephen P organization: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA – sequence: 19 givenname: Ari surname: Melnick fullname: Melnick, Ari organization: Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA – sequence: 20 givenname: Steven M surname: Kornblau fullname: Kornblau, Steven M organization: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA – sequence: 21 givenname: Markus surname: Müschen fullname: Müschen, Markus email: markus.muschen@ucsf.edu organization: Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: markus.muschen@ucsf.edu |
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| Snippet | Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast... Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast... |
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| SubjectTerms | Animals Antineoplastic Agents - pharmacology Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Cell Transformation, Neoplastic - pathology DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Dual Specificity Phosphatase 6 - genetics Dual Specificity Phosphatase 6 - metabolism Host Cell Factor C1 Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism MAP Kinase Signaling System - drug effects Membrane Proteins - antagonists & inhibitors Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Transgenic Molecular Sequence Data Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology Prognosis Protein Serine-Threonine Kinases Small Molecule Libraries - pharmacology Transcription Factors - genetics Transcription Factors - metabolism |
| Title | Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia |
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