TY - JOUR
T1 - Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia
AU - Salik, Basit
AU - Yi, Hangyu
AU - Hassan, Nunki
AU - Santiappillai, Nancy
AU - Vick, Binje
AU - Connerty, Patrick
AU - Duly, Alastair
AU - Trahair, Toby
AU - Woo, Andrew J
AU - Beck, Dominik
AU - Liu, Tao
AU - Spiekermann, Karsten
AU - Jeremias, Irmela
AU - Wang, Jianlong
AU - Kavallaris, Maria
AU - Haber, Michelle
AU - Norris, Murray D
AU - Liebermann, Dan A
AU - D'Andrea, Richard J
AU - Murriel, Christopher
AU - Wang, Jenny Y
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
U2 - 10.1016/j.ccell.2020.05.014
DO - 10.1016/j.ccell.2020.05.014
M3 - Article
C2 - 32559496
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
ER -