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JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML.

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Affiliations

  • 1. Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
      Authors
    • Karjalainen R 1
    • Pemovska T 1
    • Liu M 1
    • Javarappa KK 1
    • Majumder MM 1
    • Yadav B 1
    • Tang J 1
    • Bychkov D 1
    • Parsons A 1
    • Suvela M 1
    • Aittokallio T 1
    • Kallioniemi O 1
    • Wennerberg K 1
    • Knowles J 1
    • Heckman CA 1
    (15 authors)
  • 2. Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
      Authors
    • Popa M 2
    • Mayoral Safont M 2
    • McCormack E 2
    • Gjertsen BT 2
    (4 authors)
  • 3. Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
      Authors
    • Tamborero D 3
    (1 author)
  • 4. Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland.
      Authors
    • Kontro M 4
    • Porkka K 4
    (2 authors)

ORCIDs linked to this article

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Blood, 15 Jun 2017, 130(6):789-802
https://doi.org/10.1182/blood-2016-02-699363 PMID: 28619982 

Abstract 

The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be a result of the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the effect of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions. In the stroma-based conditions, the AML patient cells exhibited significantly reduced sensitivity to 12% of the tested compounds, including topoisomerase II, B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2), and many tyrosine kinase inhibitors (TKIs). The loss of TKI sensitivity was most pronounced in patient samples harboring FLT3 or PDGFRB alterations. In contrast, the stroma-derived conditions enhanced sensitivity to Janus kinase (JAK) inhibitors. Increased cell viability and resistance to specific drug classes in the BM stroma-derived conditions was a result of activation of alternative signaling pathways mediated by factors secreted by BM stromal cells and involved a switch from BCL2 to BCLXL-dependent cell survival. Moreover, the JAK1/2 inhibitor ruxolitinib restored sensitivity to the BCL2 inhibitor venetoclax in AML patient cells ex vivo in different model systems and in vivo in an AML xenograft mouse model. These findings highlight the potential of JAK inhibitors to counteract stroma-induced resistance to BCL2 inhibitors in AML.

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Read article at publisher's site: https://doi.org/10.1182/blood-2016-02-699363

Read article for free, from open access legal sources, via Unpaywall: https://ashpublications.org/blood/article-pdf/130/6/789/1404819/blood699363.pdfUnpaywall

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Funding 

Funders who supported this work.

Cancer Foundation Finland sr (5)

European Hematology Association (1)