Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma

Shariful Islam, Andrew L. Paek, Michael Hammer, Savithri Rangarajan, Robert Ruijtenbeek, Laurence Cooke, Eric - Weterings, Daruka Mahadevan

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 reenter 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.

Original languageEnglish (US)
Pages (from-to)35875-35890
Number of pages16
JournalOncotarget
Volume9
Issue number89
StatePublished - Nov 1 2018

Fingerprint

Polyploidy
Lymphoma, Large B-Cell, Diffuse
Aneuploidy
Recurrence
Pharmaceutical Preparations
Cell- and Tissue-Based Therapy
Therapeutics
Nuclear Fission
Cell Cycle
B-Lymphocytes
Cell Death
Aurora Kinases
M Phase Cell Cycle Checkpoints
Immune Evasion
Meiosis
Receptor Protein-Tyrosine Kinases
Vincristine
Drug Delivery Systems
T-Cell Antigen Receptor
DNA Replication

Keywords

  • Aneuploidy-polyploidy
  • Aurora kinase
  • DLBCL
  • RanGAP1
  • TPX2

ASJC Scopus subject areas

  • Oncology

Cite this

Islam, S., Paek, A. L., Hammer, M., Rangarajan, S., Ruijtenbeek, R., Cooke, L., ... Mahadevan, D. (2018). Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma. Oncotarget, 9(89), 35875-35890.

Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma. / Islam, Shariful; Paek, Andrew L.; Hammer, Michael; Rangarajan, Savithri; Ruijtenbeek, Robert; Cooke, Laurence; Weterings, Eric -; Mahadevan, Daruka.

In: Oncotarget, Vol. 9, No. 89, 01.11.2018, p. 35875-35890.

Research output: Contribution to journalArticle

Islam, S, Paek, AL, Hammer, M, Rangarajan, S, Ruijtenbeek, R, Cooke, L, Weterings, E & Mahadevan, D 2018, 'Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma', Oncotarget, vol. 9, no. 89, pp. 35875-35890.
Islam S, Paek AL, Hammer M, Rangarajan S, Ruijtenbeek R, Cooke L et al. Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma. Oncotarget. 2018 Nov 1;9(89):35875-35890.
Islam, Shariful ; Paek, Andrew L. ; Hammer, Michael ; Rangarajan, Savithri ; Ruijtenbeek, Robert ; Cooke, Laurence ; Weterings, Eric - ; Mahadevan, Daruka. / Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma. In: Oncotarget. 2018 ; Vol. 9, No. 89. pp. 35875-35890.
@article{398238f20664402dadd18fbd26d14b11,
title = "Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma",
abstract = "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 reenter 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.",
keywords = "Aneuploidy-polyploidy, Aurora kinase, DLBCL, RanGAP1, TPX2",
author = "Shariful Islam and Paek, {Andrew L.} and Michael Hammer and Savithri Rangarajan and Robert Ruijtenbeek and Laurence Cooke and Weterings, {Eric -} and Daruka Mahadevan",
year = "2018",
month = "11",
day = "1",
language = "English (US)",
volume = "9",
pages = "35875--35890",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "89",

}

TY - JOUR

T1 - Drug-induced aneuploidy and polyploidy is a mechanism of disease relapse in MYC/BCL2-addicted diffuse large B-cell lymphoma

AU - Islam, Shariful

AU - Paek, Andrew L.

AU - Hammer, Michael

AU - Rangarajan, Savithri

AU - Ruijtenbeek, Robert

AU - Cooke, Laurence

AU - Weterings, Eric -

AU - Mahadevan, Daruka

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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 reenter 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.

AB - 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 reenter 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.

KW - Aneuploidy-polyploidy

KW - Aurora kinase

KW - DLBCL

KW - RanGAP1

KW - TPX2

UR - http://www.scopus.com/inward/record.url?scp=85056578084&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056578084&partnerID=8YFLogxK

M3 - Article

VL - 9

SP - 35875

EP - 35890

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 89

ER -