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Drug-tolerant persister B-cell precursor acute lymphoblastic leukemia cells

Mingfeng Zhang, Lu Yang, David Chen, View ORCID ProfileNora Heisterkamp
doi: https://doi.org/10.1101/2023.02.28.530540
Mingfeng Zhang
Department of Systems Biology, Beckman Research Institute City of Hope, Monrovia, CA, USA
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Lu Yang
Department of Systems Biology, Beckman Research Institute City of Hope, Monrovia, CA, USA
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David Chen
Department of Systems Biology, Beckman Research Institute City of Hope, Monrovia, CA, USA
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Nora Heisterkamp
Department of Systems Biology, Beckman Research Institute City of Hope, Monrovia, CA, USA
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  • ORCID record for Nora Heisterkamp
  • For correspondence: eheisterkamp@coh.org
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Abstract

Reduced responsiveness of precursor B-acute lymphoblastic leukemia (BCP-ALL) to chemotherapy can be inferred when leukemia cells persist after 28 days of initial treatment. Survival of these long-term persister (LTP) / minimal residual disease (MRD) cells is partly due to bone marrow stromal cells that protect them under conditions of chemotherapy stress. We used RNA-seq to analyse BCP-ALL cells that survived a long-term, 30-day vincristine chemotherapy treatment while in co-culture with bone marrow stromal cells. RNAs of as many as 10% of the protein-encoding genes were differentially expressed. There was substantial overlap with genes associated with MRD cell persistence reported in other studies. The top pathway regulated in the LTP cells was that involving p53, a master regulator of a spectrum of responses relevant to drug resistance and cytotoxic drug exposure including control of autophagy. We tested a select number of genes for contribution to BCP-ALL cell survival using Cas9/CRISPR in a 2-step selection, initially for overall effect on cell fitness, followed by 21 days of exposure to vincristine. Many genes involved in autophagy and lysosomal function were found to contribute to survival both at steady-state and during drug treatment. We also identified MYH9, NCSTN and KIAA2013 as specific genes contributing to fitness of BCP-ALL cells. CD44 was not essential for growth under steady state conditions but was needed for survival of vincristine treatment. Finally, although the drug transporter ABCC1/MRP1 is not overexpressed in BCP-ALL, a functional gene was needed for DTP cells to survive treatment with vincristine. This suggests that addition of possible ABCC1 inhibitors during induction therapy could provide benefit in eradication of minimal residual disease in patients treated with a chemotherapy regimen that includes vincristine.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Email addresses: Mingfeng Zhang mingfengzhang{at}coh.org, Lu Yang luyang{at}coh.org, David Chen cweichen{at}coh.org

  • Declaration of interests: None

  • Submission declaration: The work described has not been published previously, is not under consideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out. If accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder.

  • Role of funding source: This study was partly supported in 2016/2017 by a New Idea Award to NH from the Leukemia Lymphoma Society, by NIH RO1 CA090321 and CA172040 to NH. The funding organizations had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

  • Abbreviations

    BCP-ALL
    precursor B-cell acute lymphoblastic leukemia
    DE
    differential expression
    DTP
    drug-tolerant persister
    EMDR
    environment-mediated drug resistance
    GSEA
    Gene Set Enrichment analysis
    logFc
    log2-fold change
    MAGeCK
    Model-based Analysis of Genomewide CRISPR/Cas9 Knockout
    MFI
    mean fluorescent intensity
    MRD
    minimal residual disease
    rpkm
    reads per kilobase million
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Posted March 01, 2023.
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    Drug-tolerant persister B-cell precursor acute lymphoblastic leukemia cells
    Mingfeng Zhang, Lu Yang, David Chen, Nora Heisterkamp
    bioRxiv 2023.02.28.530540; doi: https://doi.org/10.1101/2023.02.28.530540
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    Drug-tolerant persister B-cell precursor acute lymphoblastic leukemia cells
    Mingfeng Zhang, Lu Yang, David Chen, Nora Heisterkamp
    bioRxiv 2023.02.28.530540; doi: https://doi.org/10.1101/2023.02.28.530540

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