期刊
CANCER CELL
卷 38, 期 2, 页码 263-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2020.05.014
关键词
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资金
- 2018 Priority-driven Collaborative Cancer Research Scheme [1165516]
- Cancer Australia
- Leukaemia Foundation of Australia
- Tour de Cure Senior Research Grant [RSP-148-18/19]
- NIH [R01HL146664]
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.
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