This article by Karjalainen et al. investigates how the bone marrow (BM) microenvironment contributes to drug resistance in acute myeloid leukemia (AML) and whether targeting microenvironment-driven signaling can overcome this resistance. Although targeted therapies such as BCL2 inhibitors (e.g., venetoclax) and tyrosine kinase inhibitors (TKIs) show promising activity in vitro, their clinical efficacy is often limited by stromal protection within the BM niche.
Using primary AML patient samples and a large-scale ex vivo drug screening platform with 304 compounds, the authors demonstrate that BM stromal cell–derived conditioned medium (CM) significantly alters drug responses. AML cells cultured in CM show increased viability and reduced sensitivity to multiple drug classes, including topoisomerase II inhibitors, BCL2 inhibitors, and a broad range of TKIs. This resistance is particularly pronounced in genetically defined subgroups such as FLT3-ITD–mutant AML, highlighting the interaction between oncogenic signaling and microenvironmental cues.
Mechanistically, the study shows that stromal-derived cytokines, including IL-6, IL-8, GM-CSF, and G-CSF, activate intracellular signaling pathways, most notably the JAK/STAT pathway, with strong induction of STAT5 phosphorylation. This cytokine-driven signaling promotes AML cell survival and induces a shift in apoptotic dependency from BCL2 to BCLXL. Consistent with this, AML cells in stromal conditions exhibit decreased BCL2 expression and increased BCLXL/BCLXS expression, rendering them less sensitive to the BCL2-specific inhibitor venetoclax. Importantly, cytokines such as GM-CSF and G-CSF alone are sufficient to reproduce this resistance phenotype, linking microenvironmental signaling directly to altered apoptotic regulation.
In parallel, the authors show that stromal conditions reduce the efficacy of multiple TKIs, including FLT3 and PDGFR inhibitors, suggesting that cytokine-mediated signaling bypasses oncogene dependency. In contrast, sensitivity to JAK inhibitors is increased in stromal conditions, indicating that AML cells become more reliant on JAK/STAT signaling for survival in the presence of microenvironmental stimuli.
Building on these findings, the study demonstrates that combined inhibition of JAK1/2 (with ruxolitinib) and BCL2 (with venetoclax) produces strong synergistic effects specifically in stromal conditions. While venetoclax alone is ineffective in CM, the combination restores apoptosis, reduces colony-forming capacity, and effectively targets CD34⁺ leukemic progenitor cells. This synergy arises because JAK inhibition blocks cytokine-driven survival signaling and reverses the shift toward BCLXL dependence, thereby resensitizing cells to BCL2 inhibition.
In vivo validation using an AML xenograft mouse model confirms these results. Although venetoclax alone initially reduces tumor burden, relapse occurs after treatment cessation. In contrast, the combination of venetoclax and ruxolitinib leads to more sustained suppression of leukemia growth and significantly reduces tumor burden compared to single-agent treatments. These findings demonstrate that microenvironment-mediated resistance mechanisms are active in vivo and can be therapeutically targeted.
Overall, the study identifies the BM microenvironment as a critical driver of drug resistance in AML through cytokine-mediated activation of JAK/STAT signaling and reprogramming of apoptotic dependencies. It demonstrates that effective therapy requires simultaneous targeting of both intrinsic survival pathways (BCL2) and extrinsic, microenvironment-driven signaling (JAK/STAT). These findings support a combination strategy of venetoclax and JAK inhibitors as a promising approach to overcome stromal protection and improve treatment outcomes in AML.
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Karjalainen R, Pemovska T, Popa M, Liu M, Javarappa KK, Majumder MM, Yadav B, Tamborero D, Tang J, Bychkov D, Kontro M, Parsons A, Suvela M, Mayoral Safont M, Porkka K, Aittokallio T, Kallioniemi O, McCormack E, Gjertsen BT, Wennerberg K, Knowles J, Heckman CA. JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML
Blood. 2017 Aug 10;130(6):789-802. doi: 10.1182/blood-2016-02-699363. Epub 2017 Jun 15. PMID: 28619982