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

Salik, Basit; Yi, Hangyu; Hassan, Nunki; Santiappillai, Nancy; Vick, Binje; Connerty, Patrick; Duly, Alastair; Trahair, Toby; Woo, Andrew J.; Beck, Dominik; Liu, Tao; Spiekermann, Karsten; Jeremias, Irmela; Wang, Jianlong; Kavallaris, Maria; Haber, Michelle; Norris, Murray D.; Liebermann, Dan A.; D'Andrea, Richard J.; Murriel, Christopher und Wang, Jenny Y. (2020): Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia. In: Cancer Cell, Bd. 38, Nr. 2: S. 263-278

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 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 antiRSPO3 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1535-6108
• Sprache: Englisch