靶向 RSPO3-LGR4 信号通路消除急性髓系白血病白血病干细胞。
Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia.
机构信息
Cancer and Stem Cell Biology Group, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW 2052, Australia.
German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), partner site Munich, Munich, Germany; Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
出版信息
Cancer Cell. 2020 Aug 10;38(2):263-278.e6. doi: 10.1016/j.ccell.2020.05.014. Epub 2020 Jun 18.
Signals driving aberrant self-renewal in the heterogeneous leukemia stem cell (LSC) pool determine aggressiveness of acute myeloid leukemia (AML). We report that a positive modulator of canonical WNT signaling pathway, RSPO-LGR4, upregulates key self-renewal genes and is essential for LSC self-renewal in a subset of AML. RSPO2/3 serve as stem cell growth factors to block differentiation and promote proliferation of primary AML patient blasts. RSPO receptor, LGR4, is epigenetically upregulated and works through cooperation with HOXA9, a poor prognostic predictor. Blocking the RSPO3-LGR4 interaction by clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) impairs self-renewal and induces differentiation in AML patient-derived xenografts but does not affect normal hematopoietic stem cells, providing a therapeutic opportunity for HOXA9-dependent leukemia.
信号驱动异质性白血病干细胞（LSC）池中的异常自我更新决定了急性髓细胞白血病（AML）的侵袭性。我们报告称，经典 WNT 信号通路的阳性调节剂 RSPO-LGR4 上调关键自我更新基因，并且对于 AML 中的一部分 LSC 自我更新是必需的。RSPO2/3 作为干细胞生长因子，可阻止分化并促进原发性 AML 患者原始细胞的增殖。RSPO 受体 LGR4 通过表观遗传上调，并与 HOXA9 协同作用，后者是一个预后不良的预测因子。通过临床级别的抗 RSPO3 抗体（OMP-131R10/rosmantuzumab）阻断 RSPO3-LGR4 相互作用会损害 AML 患者来源异种移植物中的自我更新并诱导分化，但不影响正常造血干细胞，为 HOXA9 依赖性白血病提供了治疗机会。
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