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RSPO3-LGR4信号通路可作为急性髓系白血病治疗的新靶点
作者:小柯机器人 发布时间:2020/6/20 16:58:49

澳大利亚新南威尔士大学Jenny Y. Wang课题组发现,在急性髓样白血病(AML)中靶向RSPO3-LGR4信号通路可清除白血病干细胞。这一研究成果于2020年6月18日在线发表于《癌细胞》。

研究人员发现经典WNT信号通路的正调节因子RSPO LGR4上调关键的自我更新基因,这是部分AML中异种白血病干细胞(LSC)自我更新必不可少的。RSPO2 / 3作为干细胞生长因子来阻止分化并促进原发性AML患者基细胞的增殖。表观遗传会导致RSPO受体LGR4上调,并与不良预后指标HOXA9协同工作。

使用临床级抗RSPO3抗体(OMP-131R10 / rosmantuzumab)阻断RSPO3-LGR4相互作用会损害LSC的自我更新,并诱导AML患者来源的异种移植物分化,但不会影响正常的造血干细胞,这为HOXA9-依赖性白血病的治疗提供了新思路。

据了解,LSC库中诱导异常自我更新的信号决定了AML的侵袭性。

附:英文原文

Title: Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia

Author: Basit Salik, Hangyu Yi, Nunki Hassan, Nancy Santiappillai, Binje Vick, Patrick Connerty, Alastair Duly, Toby Trahair, Andrew J. Woo, Dominik Beck, Tao Liu, Karsten Spiekermann, Irmela Jeremias, Jianlong Wang, Maria Kavallaris, Michelle Haber, Murray D. Norris, Dan A. Liebermann, Richard J. DAndrea, Christopher Murriel, Jenny Y. Wang

Issue&Volume: 2020-06-18

Abstract: Signals driving aberrant self-renewal in the heterogeneous leukemia stem cell (LSC)pool determine aggressiveness of acute myeloid leukemia (AML). We report that a positivemodulator of canonical WNT signaling pathway, RSPO-LGR4, upregulates key self-renewalgenes and is essential for LSC self-renewal in a subset of AML. RSPO2/3 serve as stemcell growth factors to block differentiation and promote proliferation of primaryAML patient blasts. RSPO receptor, LGR4, is epigenetically upregulated and works throughcooperation with HOXA9, a poor prognostic predictor. Blocking the RSPO3-LGR4 interactionby clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) impairs self-renewaland induces differentiation in AML patient-derived xenografts but does not affectnormal hematopoietic stem cells, providing a therapeutic opportunity for HOXA9-dependentleukemia.

DOI: 10.1016/j.ccell.2020.05.014

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30264-6

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx