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

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 journal › Article › peer-review

91 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 language	English (US)
Pages (from-to)	114-128
Number of pages	15
Journal	Cancer Cell
Volume	28
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2015.05.008
State	Published - Jul 13 2015
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2015.05.008

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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

Shojaee, S, Caeser, R, Buchner, M, Park, E, Swaminathan, S, Hurtz, C, Geng, H, Chan, LN, Klemm, L, Hofmann, WK, Qiu, YH, Zhang, N, Coombes, KR, Paietta, E, Molkentin, J, Koeffler, HP, Willman, CL, Hunger, SP, Melnick, A, Kornblau, SM & Müschen, M 2015, 'Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia', Cancer Cell, vol. 28, no. 1, pp. 114-128. https://doi.org/10.1016/j.ccell.2015.05.008

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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. 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.",

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

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doi = "10.1016/j.ccell.2015.05.008",

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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

PY - 2015/7/13

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

Abstract

ASJC Scopus subject areas

UN SDGs

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