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 Murriel; Jenny Y Wang

doi:10.1016/j.ccell.2020.05.014

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

UWA Centre for Medical Research (affiliated with the Harry Perkins Institute of Medical Research)

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

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 language	English
Journal	Cancer Cell
DOIs	https://doi.org/10.1016/j.ccell.2020.05.014
Publication status	E-pub ahead of print - 1 Jun 2020

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10.1016/j.ccell.2020.05.014

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Salik, B., Yi, H., Hassan, N., Santiappillai, N., Vick, B., Connerty, P., Duly, A., Trahair, T., Woo, A. J., Beck, D., Liu, T., Spiekermann, K., Jeremias, I., Wang, J., Kavallaris, M., Haber, M., Norris, M. D., Liebermann, D. A., D'Andrea, R. J., ... Wang, J. Y. (2020). Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia. Cancer Cell. https://doi.org/10.1016/j.ccell.2020.05.014

Salik, Basit ; Yi, Hangyu ; Hassan, Nunki ; Santiappillai, Nancy ; Vick, Binje ; Connerty, Patrick ; Duly, Alastair ; Trahair, Toby ; Woo, Andrew J ; Beck, Dominik ; Liu, Tao ; Spiekermann, Karsten ; Jeremias, Irmela ; Wang, Jianlong ; Kavallaris, Maria ; Haber, Michelle ; Norris, Murray D ; Liebermann, Dan A ; D'Andrea, Richard J ; Murriel, Christopher ; Wang, Jenny Y. / Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia. In: Cancer Cell. 2020.

@article{34b33b60582b4bce8479acaeeee7358a,

title = "Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia",

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.",

author = "Basit Salik and Hangyu Yi and Nunki Hassan and Nancy Santiappillai and Binje Vick and Patrick Connerty and Alastair Duly and Toby Trahair and Woo, {Andrew J} and Dominik Beck and Tao Liu and Karsten Spiekermann and Irmela Jeremias and Jianlong Wang and Maria Kavallaris and Michelle Haber and Norris, {Murray D} and Liebermann, {Dan A} and D'Andrea, {Richard J} and Christopher Murriel and Wang, {Jenny Y}",

year = "2020",

month = jun,

day = "1",

doi = "10.1016/j.ccell.2020.05.014",

language = "English",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

}

Salik, B, Yi, H, Hassan, N, Santiappillai, N, Vick, B, Connerty, P, Duly, A, Trahair, T, Woo, AJ, Beck, D, Liu, T, Spiekermann, K, Jeremias, I, Wang, J, Kavallaris, M, Haber, M, Norris, MD, Liebermann, DA, D'Andrea, RJ, Murriel, C & Wang, JY 2020, 'Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia', Cancer Cell. https://doi.org/10.1016/j.ccell.2020.05.014

Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia. / Salik, Basit; Yi, Hangyu; Hassan, Nunki; Santiappillai, Nancy; Vick, Binje; Connerty, Patrick; Duly, Alastair; Trahair, Toby; Woo, Andrew J; Beck, Dominik; Liu, Tao; Spiekermann, Karsten; Jeremias, Irmela; Wang, Jianlong; Kavallaris, Maria; Haber, Michelle; Norris, Murray D; Liebermann, Dan A; D'Andrea, Richard J; Murriel, Christopher; Wang, Jenny Y.

In: Cancer Cell, 01.06.2020.

Research output: Contribution to journal › Article › peer-review

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 -

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

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