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

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

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

Seyedmehdi Shojaee, Elisabeth Paietta + Show 19 more

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https://doi.org/10.1016/j.ccell.2015.05.008

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Journal: Cancer Cell	Publication Date: Jun 11, 2015
Citations: 109	License type: publisher-specific-oa

Affiliation: University of California, San Francisco, Albert Einstein College of Medicine, The University of Texas MD Anderson Cancer Center, University of Cambridge, Cornell University, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, University of Cincinnati, Children's Hospital of Philadelphia, Cedars-Sinai Medical Center, National University Cancer Institute, Singapore, National University of Singapore, Heidelberg University, New Mexico Cancer Center, University of New Mexico

#pre-B Cells #Patient-derived pre-B Acute Lymphoblastic Leukemia + Show 8 more

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Abstract

Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation ofoncogenes 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 ofErk 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 modelsfor 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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