Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma
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Shariful Islam1, Andrew L. Paek2, Michael Hammer3, Savithri Rangarajan4, Robert Ruijtenbeek4, Laurence Cooke5, Eric Weterings6 and Daruka Mahadevan5
1Cancer Biology GIDP, University of Arizona Cancer Center, Tucson, AZ, USA
2Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, USA
3Division of Biotechnology, University of Arizona Cancer Center, Tucson, AZ, USA
4PamGene International B.V., 's-Hertogenbosch, The Netherlands
5Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA
6Department of Radiation Oncology, University of Arizona, Tucson, AZ, USA
Daruka Mahadevan, email: [email protected]
Keywords: DLBCL; aurora kinase; aneuploidy-polyploidy; TPX2; RanGAP1
Received: August 22, 2018 Accepted: October 06, 2018 Published: November 13, 2018
Double-hit (DH) or double-expresser (DE) lymphomas are high-grade diffuse large B-cell lymphomas (DLBCL) that are mostly incurable with standard chemo-immunotherapy due to treatment resistance. The generation of drug-induced aneuploid/polyploid (DIAP) cells is a common effect of anti-DLBCL therapies (e.g. vincristine, doxorubicin). DIAP cells are thought to be responsible for treatment resistance, as they are capable of re-entering the cell cycle during off-therapy periods. Previously we have shown that combination of alisertib plus ibrutinib plus rituximab can partially abrogate DIAP cells and induce cell death. Here, we provide evidence that DIAP cells can re-enter the cell cycle and escape cell death during anti-DLBCL treatment. We also discuss MYC/BCL2 mediated molecular mechanism that underlie treatment resistance. We isolated aneuploid/polyploid populations of DH/DE-DLBCL cells after treatment with the aurora kinase (AK) inhibitor alisertib. Time-lapse microscopy of single polyploid cells revealed that following drug removal, a subset of these DIAP cells divide and proliferate by reductive cell divisions, including multipolar mitosis, meiosis-like nuclear fission and budding. Genomic, proteomic, and kinomic profiling demonstrated that alisertib-induced aneuploid/polyploid cells up-regulate DNA damage, DNA replication and immune evasion pathways. In addition, we identified amplified receptor tyrosine kinase and T-cell receptor signaling, as well as MYC-mediated dysregulation of the spindle assembly checkpoints RanGAP1, TPX2 and KPNA2. We infer that these factors contribute to treatment resistance of DIAP cells. These findings provide opportunities to develop novel DH/DE-DLBCL therapies, specifically targeting DIAP cells.
MYC mediated upregulation of TPX2, KPNA2 and RanGAP1 dysregulate the spindle assembly checkpoint in drug-induced polyploid cells.
Drug-induced polyploid cells re-enter the cell cycle via multipolar mitosis, fission or budding, a mechanism of disease relapse.
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