TY - JOUR
T1 - Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia
AU - Shojaee, Seyedmehdi
AU - Caeser, Rebecca
AU - Buchner, Maike
AU - Park, Eugene
AU - Swaminathan, Srividya
AU - Hurtz, Christian
AU - Geng, Huimin
AU - Chan, Lai N.
AU - Klemm, Lars
AU - Hofmann, Wolf Karsten
AU - Qiu, Yi Hua
AU - Zhang, Nianxiang
AU - Coombes, Kevin R.
AU - Paietta, Elisabeth
AU - Molkentin, Jeffery
AU - Koeffler, H. Phillip
AU - Willman, Cheryl L.
AU - Hunger, Stephen P.
AU - Melnick, Ari
AU - Kornblau, Steven M.
AU - Müschen, Markus
N1 - Funding Information:
We thank Dr. Kenneth M. Murphy, St. Louis, MO and Dr. Gail R. Martin, San Francisco, CA for sharing Etv5 −/− and Spry2 fl/fl mice with us. This work is supported by grants from the NIH/NCI through R01CA137060, R01CA139032, R01CA169458, R01CA172558, and R01CA157644 (to M.M.); grants from the Leukemia and Lymphoma Society (to M.M.); the California Institute for Regenerative Medicine through TR02-1816 (M.M.); and the William Lawrence and Blanche Hughes Foundation and a Leukemia and Lymphoma Society SCOR grant (LLS-7005-11). M.M. is a Scholar of The Leukemia and Lymphoma Society and a Senior Investigator of the Wellcome Trust.
Publisher Copyright:
© 2015 Elsevier Inc..
PY - 2015/7/13
Y1 - 2015/7/13
N2 - 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. Shojaee etal. show that successful transformation of pre-B cells to pre-B acute lymphoblastic leukemia (ALL) requires negative feedback regulation of Erk signaling and inhibiting this feedback selectively kills pre-B ALL cells, suggesting negative feedback regulation of oncogenes as a vulnerability in human ALL.
AB - 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. Shojaee etal. show that successful transformation of pre-B cells to pre-B acute lymphoblastic leukemia (ALL) requires negative feedback regulation of Erk signaling and inhibiting this feedback selectively kills pre-B ALL cells, suggesting negative feedback regulation of oncogenes as a vulnerability in human ALL.
UR - http://www.scopus.com/inward/record.url?scp=84937523707&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937523707&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2015.05.008
DO - 10.1016/j.ccell.2015.05.008
M3 - Article
C2 - 26073130
AN - SCOPUS:84937523707
SN - 1535-6108
VL - 28
SP - 114
EP - 128
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -
