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. KornblauMarkus Müschen

Research output: Contribution to journalArticle

52 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)114-128
Number of pages15
JournalCancer Cell
Volume28
Issue number1
DOIs
StatePublished - Jul 13 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Shojaee, S., Caeser, R., Buchner, M., Park, E., Swaminathan, S., Hurtz, C., Geng, H., Chan, L. N., Klemm, L., Hofmann, W. K., Qiu, Y. H., Zhang, N., Coombes, K. R., Paietta, E., Molkentin, J., Koeffler, H. P., Willman, C. L., Hunger, S. P., Melnick, A., ... Müschen, M. (2015). Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia. Cancer Cell, 28(1), 114-128. https://doi.org/10.1016/j.ccell.2015.05.008