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

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 or 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.

The bone marrow microenvironment in health and disease at a glance

“…The second approach of targeting leukemia cell intrinsic pathways (partly reviewed in Krause and Scadden, 2015) includes the inhibition of Axl and its interaction with Gas6 in AML (Ben-Batalla et al, 2013), for instance with the compound MYD1-72 (Kariolis et al, 2017), or the inhibition of CCL3 (Frisch et al, 2012;Schepers et al, 2013), placental growth factor (PlGF; Schmidt et al, 2011), IL-6 (Welner et al, 2015) and Jak2 in myeloproliferative neoplasia (MPN) (Meyer et al, 2015) and AML (Karjalainen et al, 2017). Other possible therapeutic strategies are inhibition of NF-κB, which lies downstream of the vascular cell adhesion molecule (VCAM)-1-integrin-β1 signaling axis, of various cytokines or their receptors (Jacamo et al, 2014) or targeting of CD44 (Erb et al, 2014;Singh et al, 2013).…”

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

“…In AML, the high rate of relapse may in part be a result of the inability of current treatments to effectively overcome the protective influence of the BM niche. 5,46 In fact, it has been recently shown that BM mesenchymal stromal cells (BM-MSCs) derived from diagnostic AML patients are strong immunomodulators and provide similar or even higher chemoprotection of AML cells to cytarabine/idarubicin than normal BM-MSCs. 5 Therefore, new compounds or improved combinatory regimens targeting the interaction between the BM microenvironment and AML leukemic cells are very attractive candidates.…”

Biology-Driven Approaches to Prevent and Treat Relapse of Myeloid Neoplasia after Allogeneic Hematopoietic Stem Cell Transplantation

“…The finding that normal HSCs and leukemia stem cells (LSCs) occupy the same niche and that HSCs can outperform LSCs [61] supports the concept that modification of the bone marrow stroma can improve the efficacy of allo-HCT. In accordance with this idea, preclinical data have been published suggesting that interference with the interaction of leukemia and stroma cells may provide a new approach to improve treatment [62]. However, clinical data on the specific use to prevent or treat relapse after allo-HCT are lacking.…”