JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML
JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML
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DOI：
10.1182/blood-2016-02-699363
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发表时间：
2017-08-10
期刊：
影响因子：
20.3
通讯作者：
Heckman, Caroline A.
中科院分区：
文献类型：
--
作者：
Karjalainen, Riikka;Pemovska, Tea;Heckman, Caroline A.
骨髓（BM）提供了一个保护性的微环境，以支持白血病细胞的存活，并影响其对治疗药物的反应。在急性髓性白血病（AML）中，高复发率可能部分是由于目前的治疗无法有效克服BM生态位的保护性影响。为了更好地了解骨髓微环境对AML药物反应的影响，我们对304种抑制剂进行了全面评估，包括批准和研究药物，比较了原代AML细胞在骨髓基质衍生和标准培养条件下的离体反应。在基于基质的条件下，AML患者细胞对12%的测试化合物表现出显著降低的敏感性，包括拓扑异构酶II、B细胞慢性淋巴细胞白血病/淋巴瘤2（BCL 2）和许多酪氨酸激酶抑制剂（TKI）。TKI敏感性的丧失在携带FLT 3或PDGFRB改变的患者样本中最为明显。相比之下，基质来源的条件增强了对Janus激酶（JAK）抑制剂的敏感性。在BM基质衍生条件下，细胞活力和对特定药物类别的耐药性增加是由BM基质细胞分泌的因子介导的替代信号通路激活的结果，并涉及从BCL 2到BCLXL依赖性细胞生存的转变。此外，JAK 1/2抑制剂ruxolitinib在不同模型系统中的离体AML患者细胞和在AML异种移植小鼠模型中的体内恢复了对BCL 2抑制剂venetoclax的敏感性。这些发现强调了JAK抑制剂抵消AML中基质诱导的对BCL 2抑制剂的耐药性的潜力。
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.