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

Riikka Karjalainen, Tea Pemovska, Mihaela Popa, Minxia Liu, Komal K. Javarappa, Muntasir M. Majumder, Bhagwan Yadav, David Tamborero, Jing Tang, Dmitrii Bychkov, Mika Kontro, Alun Parsons, Minna Suvela, Mireia Mayoral Safont, Kimmo Porkka, Tero Aittokallio, Olli Kallioniemi, Emmet McCormack, Bjørn T. Gjertsen, Krister Wennerberg, Jonathan Knowles and Caroline A. Heckman

Key points

  • BM stroma-derived conditions protect AML patient cells against topoisomerase II and BCL2 inhibitors, as well as several classes of TKIs.

  • JAK1/2 inhibitor ruxolitinib reverses cytoprotection against BCL2 antagonist venetoclax, suggesting a novel combinatorial treatment.

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 due to the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the impact 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 CLL/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 due to 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.

  • Submitted February 24, 2016.
  • Accepted May 31, 2017.