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Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors

Leukemia volume 26, pages 1140–1143 (2012)Cite this article

The introduction of imatinib just over ten years ago revolutionized chronic myeloid leukemia (CML) therapy, making long-term survival a reality for the majority of newly diagnosed patients. Unfortunately, residual disease remains detectable in most patients, and even patients with undetectable BCR–ABL (complete molecular response) have a substantial risk of disease recurrence upon discontinuation of imatinib.1 Studies to understand the mechanism(s) underlying CML persistence in spite of ongoing, successful TKI-based disease management have mainly focused on cell-intrinsic mechanisms. However, there is compelling evidence that the microenvironment has an important role in resistance to chemotherapy by providing critical survival cues to cells.2 Therefore, we hypothesized that extrinsic factors may also contribute to CML disease persistence despite effective inhibition of BCR–ABL kinase activity by imatinib and second generation ABL inhibitors.

To investigate these extrinsic survival factors in a more physiologic context, we used immortalized human bone marrow stromal cells as a model of the microenvironment.3 We found that conditioned media (CM) from HS-5, but not HS-23 or HS-27a, enhanced survival of CML cell lines in the presence of imatinib, dasatinib and nilotinib (Supplementary Figure 1), consistent with previous reports.4, 5 Furthermore, we found that CML CD34+ cells co-cultured with HS-5 cells, or cultured in transwells over HS-5 cells, also attenuated the effects of imatinib on colony formation (Supplementary Figure 1). These data suggested that soluble factors may be responsible for HS-5-mediated protection from TKIs. We quantified the relative abundance of several cytokines in CM from the three human stromal cell lines to identify putative protective factors and found high concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), growth-related oncogene 1 (GRO1), monocyte chemotactic protein 1 (MCP-1), monocyte chemotactic protein 3 (MCP-3), granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) in HS-5 CM compared with HS-23 and HS-27a CM (data not shown). As several of these cytokines (G-CSF, GM-CSF, and IL-6) signal through JAK2,6 we used CYT387, a JAK1/JAK2 inhibitor, and TG101209, a relatively specific JAK2 inhibitor,7, 8 to interrogate the role of JAK2 in protection of CML cells by HS-5 CM.

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Acknowledgements

We thank Chris Koontz, Sarah Bowden and Suzanne Wickens for administrative support. This study was supported by NHLBI grant HL082978-01 (MWD) and the Leukemia and Lymphoma Society (MWD). ET is supported by T32 Molecular Hematology Training Grant HL007781-18.

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Author notes

  1. R MacKenzie, J Snead and A Agarwal: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    E Traer, R MacKenzie, J Snead, A Agarwal & B J Druker

  2. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    A M Eiring, T O'Hare & M W Deininger

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  1. E Traer
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  2. R MacKenzie
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Correspondence to M W Deininger.

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Traer, E., MacKenzie, R., Snead, J. et al. Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors. Leukemia 26, 1140–1143 (2012). https://doi.org/10.1038/leu.2011.325

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