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

Area of Science:

• Hematology
• Molecular Biology
• Cancer Research

Background:

• Aberrant self-renewal of leukemia stem cells (LSCs) dictates acute myeloid leukemia (AML) aggressiveness.
• The heterogeneity of the LSC pool presents challenges in AML treatment.

Purpose of the Study:

• To investigate the role of RSPO-LGR4 signaling in LSC self-renewal and AML progression.
• To evaluate the therapeutic potential of targeting the RSPO3-LGR4 interaction in AML.

Main Methods:

• Analysis of RSPO-LGR4 signaling in primary AML patient samples.
• Assessment of RSPO2/3 as stem cell growth factors.
• Evaluation of the anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) in AML patient-derived xenografts.
• Investigation of LGR4 and HOXA9 cooperation.

Main Results:

• RSPO-LGR4 signaling positively modulates key self-renewal genes, essential for LSC self-renewal in a subset of AML.
• RSPO2/3 act as growth factors, inhibiting differentiation and promoting proliferation of AML blasts.
• Epigenetic upregulation of LGR4 cooperates with the poor prognostic marker HOXA9.
• Targeting RSPO3-LGR4 interaction with an anti-RSPO3 antibody impaired LSC self-renewal and induced differentiation in AML xenografts.

Conclusions:

• The RSPO3-LGR4 axis is a critical driver of self-renewal in a subset of AML, particularly HOXA9-dependent leukemia.
• The anti-RSPO3 antibody demonstrates therapeutic potential by selectively targeting LSCs without affecting normal hematopoietic stem cells.
• This provides a promising therapeutic strategy for AML patients with HOXA9-driven disease.