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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Bibliographic Details
Published in:	Cancer cell Vol. 28; no. 1; pp. 114 - 128
Main Authors:	Shojaee, Seyedmehdi, Caeser, Rebecca, Buchner, Maike, Park, Eugene, Swaminathan, Srividya, Hurtz, Christian, Geng, Huimin, Chan, Lai N, Klemm, Lars, Hofmann, Wolf-Karsten, Qiu, Yi Hua, Zhang, Nianxiang, Coombes, Kevin R, Paietta, Elisabeth, Molkentin, Jeffery, Koeffler, H Phillip, Willman, Cheryl L, Hunger, Stephen P, Melnick, Ari, Kornblau, Steven M, Müschen, Markus
Format:	Journal Article
Language:	English
Published:	United States 13.07.2015
Subjects:	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
ISSN:	1878-3686
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1878-3686
DOI:	10.1016/j.ccell.2015.05.008