Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia

Seyedmehdi Shojaee; Rebecca Caeser; Maike Buchner; Eugene Park; Srividya Swaminathan; Christian Hurtz; Huimin Geng; Lai N Chan; Lars Klemm; Wolf-Karsten Hofmann; Yi Hua Qiu; Nianxiang Zhang; Kevin R Coombes; Elisabeth Paietta; Jeffery Molkentin; H Phillip Koeffler; Cheryl L Willman; Stephen P Hunger; Ari Melnick; Steven M Kornblau; Markus Müschen

doi:10.1016/j.ccell.2015.05.008

Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia

Cancer Cell. 2015 Jul 13;28(1):114-28. doi: 10.1016/j.ccell.2015.05.008. Epub 2015 Jun 11.

Authors

Seyedmehdi Shojaee¹, Rebecca Caeser², Maike Buchner¹, Eugene Park³, Srividya Swaminathan¹, Christian Hurtz¹, Huimin Geng¹, Lai N Chan¹, Lars Klemm¹, Wolf-Karsten Hofmann⁴, Yi Hua Qiu⁵, Nianxiang Zhang⁶, Kevin R Coombes⁶, Elisabeth Paietta⁷, Jeffery Molkentin⁸, H Phillip Koeffler⁹, Cheryl L Willman¹⁰, Stephen P Hunger¹¹, Ari Melnick¹², Steven M Kornblau⁵, Markus Müschen¹³

Affiliations

¹ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
² Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK.
³ Department of Haematology, University of Cambridge, Cambridge CB2 0AH, UK.
⁴ III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Heidelberg 68167, Germany.
⁵ Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Albert Einstein College of Medicine, Bronx, NY 10466, USA.
⁸ Howard Hughes Medical Institute and Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH 45247, USA.
⁹ 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.
¹⁰ Department of Pathology, University of New Mexico Cancer Center, Albuquerque, NM 87102, USA.
¹¹ Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹² Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
¹³ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: markus.muschen@ucsf.edu.

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.

MeSH terms

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

Substances

Antineoplastic Agents
DNA-Binding Proteins
Etv5 protein, mouse
Host Cell Factor C1
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Small Molecule Libraries
Transcription Factors
Protein Serine-Threonine Kinases
Spry2 protein, mouse
Dual Specificity Phosphatase 6
Dusp6 protein, mouse

Associated data

GEO/GSE21664
GEO/GSE23743
GEO/GSE34832
GEO/GSE34833
GEO/GSE34834

Abstract

MeSH terms

Substances

Associated data

Grants and funding