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

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 MurrielJenny Y Wang

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
JournalCancer Cell
DOIs
Publication statusE-pub ahead of print - 1 Jun 2020

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