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MYC Dysregulates Mitotic Spindle Function Creating a Dependency on TPX2

Julia Rohrberg, Alexndra Corella, Moufida Taileb, Seda Kilinc, Marie-Lena Jokisch, Roman Camarda, Alicia Zhou, Sanjeev Balakrishnan, Aaron N. Chang, View ORCID ProfileAndrei Goga
doi: https://doi.org/10.1101/272336
Julia Rohrberg
University of California, San Francisco
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Alexndra Corella
University of California, San Francisco
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Moufida Taileb
University of California, San Francisco
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Seda Kilinc
University of California, San Francisco
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Marie-Lena Jokisch
University of California, San Francisco
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Roman Camarda
University of California, San Francisco
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Alicia Zhou
University of California, San Francisco
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Sanjeev Balakrishnan
University of California, San Francisco
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Aaron N. Chang
University of California, San Francisco
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Andrei Goga
University of California, San Francisco
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  • ORCID record for Andrei Goga
  • For correspondence: andrei.goga@ucsf.edu
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Abstract

The MYC oncogene promotes tumorigenesis in part by facilitating cell cycle entry thus driving cellular proliferation. Tumors that overexpress MYC frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers, rapid tumor evolution, and poor patient outcome. While the role of MYC in overcoming the G1/S checkpoint is well established, it remains poorly understood whether MYC induces chromosomal instability (CIN). Here, we identify a direct influence of MYC on mitotic progression. MYC overexpression induces defects in microtubule nucleation and spindle assembly, promoting chromosome segregation defects, micronuclei and CIN. We examined which mitotic regulators are required for the survival of MYC-overexpressing cells and found a reliance on high TPX2 expression. TPX2, a master microtubule regulator, is overexpressed together with MYC in multiple cell lines, in mouse tumor models and in aggressive human breast cancers. High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with deregulated MYC, whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Importantly, attenuation of MYC expression reverses the mitotic defects observed, even in established tumor cell lines, implicating an ongoing role for high MYC in the persistence of a CIN phenotype in tumors. Here, we implicate the MYC oncogene as a regulator of spindle assembly and dynamics and identify a new MYC-TPX2 synthetic-lethal interaction that could represent a future therapeutic strategy in MYC-overexpressing cancers. Our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.

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Posted April 05, 2018.
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MYC Dysregulates Mitotic Spindle Function Creating a Dependency on TPX2
Julia Rohrberg, Alexndra Corella, Moufida Taileb, Seda Kilinc, Marie-Lena Jokisch, Roman Camarda, Alicia Zhou, Sanjeev Balakrishnan, Aaron N. Chang, Andrei Goga
bioRxiv 272336; doi: https://doi.org/10.1101/272336
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MYC Dysregulates Mitotic Spindle Function Creating a Dependency on TPX2
Julia Rohrberg, Alexndra Corella, Moufida Taileb, Seda Kilinc, Marie-Lena Jokisch, Roman Camarda, Alicia Zhou, Sanjeev Balakrishnan, Aaron N. Chang, Andrei Goga
bioRxiv 272336; doi: https://doi.org/10.1101/272336

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