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

• DOI: 10.1016/j.ccell.2020.05.014
• Publication Date: 2020-06-18T14:41:01Z
• Authors: 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. D'Andrea; Christopher Murriel; Jenny Y. Wang
• Keywords: LGR5

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.