The heterogeneous response of acute myeloid leukemia (AML) to current anti-leukemic therapies is only partially explained by mutational heterogeneity. We previously identified GPR56 as a surface marker associated with poor outcome across genetic groups, which characterizes two leukemia stem cell (LSC)-enriched compartments with different self-renewal capacities. How these compartments self-renew remained unclear. Here, we show that GPR56+ LSC compartments are promoted in a complex network involving epithelial-to-mesenchymal transition (EMT) regulators besides Rho, Wnt, and Hedgehog (Hh) signaling. Unexpectedly, Wnt pathway inhibition increased the more immature, slowly cycling GPR56+ CD34+ fraction and Hh/EMT gene expression, while Wnt activation caused opposite effects. Our data suggest that the crucial role of GPR56 lies in its ability to co-activate these opposing signals, thus ensuring the constant supply of both LSC subsets. We show that CDK7 inhibitors suppress both LSC-enriched subsets in vivo and synergize with the Bcl-2 inhibitor venetoclax. Our data establish reciprocal transition between LSC compartments as a novel concept underlying the poor outcome in GPR56high AML and propose combined CDK7 and Bcl-2 inhibition as LSC-directed therapy in this disease.

中文翻译：

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CDK7/12/13 抑制作用靶向振荡的白血病干细胞网络，并与急性髓性白血病中的 venetoclax 协同作用。

急性髓性白血病 (AML) 对当前抗白血病治疗的异质反应仅部分地由突变异质性解释。我们之前将 GPR56 鉴定为与跨基因组的不良结果相关的表面标志物，其表征了两个具有不同自我更新能力的富含白血病干细胞 (LSC) 的隔室。这些隔间如何自我更新仍不清楚。在这里，我们展示了 GPR56+ LSC 隔间在一个复杂的网络中得到促进，该网络除了 Rho、Wnt 和 Hedgehog (Hh) 信号传导外，还涉及上皮间质转化 (EMT) 调节剂。出乎意料的是，Wnt 通路抑制增加了更不成熟的、缓慢循环的 GPR56+ CD34+ 部分和 Hh/EMT 基因表达，而 Wnt 激活导致相反的效果。我们的数据表明，GPR56 的关键作用在于它能够共同激活这些相反的信号，从而确保两个 LSC 子集的持续供应。我们显示 CDK7 抑制剂抑制体内富含 LSC 的亚群，并与 Bcl-2 抑制剂 venetoclax 协同作用。我们的数据确立了 LSC 隔室之间的相互转换作为 GPR56high AML 不良结果的一个新概念，并建议将 CDK7 和 Bcl-2 联合抑制作为 LSC 定向治疗这种疾病。