| Literature DB >> 32559496 |
Basit Salik1, Hangyu Yi1, Nunki Hassan1, Nancy Santiappillai1, Binje Vick2, Patrick Connerty1, Alastair Duly1, Toby Trahair3, Andrew J Woo4, Dominik Beck5, Tao Liu3, Karsten Spiekermann6, Irmela Jeremias7, Jianlong Wang8, Maria Kavallaris9, Michelle Haber3, Murray D Norris3, Dan A Liebermann10, Richard J D'Andrea11, Christopher Murriel12, Jenny Y Wang13.
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.Entities:
Keywords: AML; HOXA9; LGR4; LSC; RSPO; WNT/β-catenin; acute myeloid leukemia; leukemia stem cells; self-renewal; signaling pathway
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Year: 2020 PMID： 32559496 DOI： 10.1016/j.ccell.2020.05.014
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743