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

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

81 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 language	English
Pages (from-to)	263-278.e6
Journal	Cancer Cell
Volume	38
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2020.05.014
State	Published - 10 Aug 2020
Externally published	Yes

Keywords

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

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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, 38(2), 263-278.e6. https://doi.org/10.1016/j.ccell.2020.05.014

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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.",

keywords = "AML, HOXA9, LGR4, LSC, RSPO, WNT/β-catenin, acute myeloid leukemia, leukemia stem cells, self-renewal, signaling pathway",

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.}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = aug,

day = "10",

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

language = "English",

volume = "38",

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journal = "Cancer Cell",

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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, vol. 38, no. 2, pp. 263-278.e6. https://doi.org/10.1016/j.ccell.2020.05.014

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 - 2020/8/10

Y1 - 2020/8/10

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.

KW - AML

KW - HOXA9

KW - LGR4

KW - LSC

KW - RSPO

KW - WNT/β-catenin

KW - acute myeloid leukemia

KW - leukemia stem cells

KW - self-renewal

KW - signaling pathway

UR - http://www.scopus.com/inward/record.url?scp=85088944709&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2020.05.014

DO - 10.1016/j.ccell.2020.05.014

M3 - Article

C2 - 32559496

AN - SCOPUS:85088944709

SN - 1535-6108

VL - 38

SP - 263-278.e6

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

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

Abstract

Keywords

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