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 journalArticlepeer-review

64 Scopus citations

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
Pages (from-to)263-278.e6
JournalCancer Cell
Volume38
Issue number2
DOIs
StatePublished - 10 Aug 2020
Externally publishedYes

Keywords

  • AML
  • HOXA9
  • LGR4
  • LSC
  • RSPO
  • WNT/β-catenin
  • acute myeloid leukemia
  • leukemia stem cells
  • self-renewal
  • signaling pathway

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