RSPO2 inhibits BMP signaling to promote self-renewal in acute myeloid leukemia

Abstract

Highlights d RSPO2 is a regulator of AML cell self-renewal d RSPO2 acts as a BMP antagonist instead of as a WNT agonist in AML d High RSPO2 expression is a marker for adverse prognosis in AML

Uncoupling the BMP receptor antagonist function from the WNT agonist function of R-spondin 2 using the inhibitory peptide dendrimer RWd

“…We recently showed that RSPO2 inhibits BMP signalling in AML cells to maintain self-renewal and prevent differentiation independent of WNT signalling (26). We therefore asked whether RW d could reduce endogenous RSPO2 activity of THP-1 AML cells to upregulate BMP signalling and thereby induce monocyte to macrophage (CD11B + ) differentiation.…”

“…Given that RSPO2 antagonizes BMP4 signalling (14,26), we expected that RW d derepresses RSPO2-mediated inhibition of BMP4 signalling. To test this prediction, we employed human hepatocellular carcinoma (HEPG2) cells, which harbor very low endogenous RSPO2 expression (14).…”

“…In AML, RSPO2 acts as autocrine growth factor to maintain self-renewal and cell proliferation (26). Hence, inhibition of RSPO2 by RW d may provide a therapeutic benefit in AML, by derepressing BMP signalling and reducing cancer cell viability.…”

“…We showed that among the four RSPOs, only RSPO2 and RSPO3 are bifunctional, activating WNT-and inhibiting BMP J o u r n a l P r e -p r o o f signalling. Mechanistically, RSPO2 specifically interacts with BMPR1A and tethers it to ZNRF3 in an LGR-independent manner to trigger endocytosis and degradation of BMPR1A (14,26).…”

“…In vivo support for a role of RSPO2 as selective BMP antagonist comes from early Xenopus embryogenesis, where RSPO2 cooperates with other BMP antagonists of the Spemann organizer to inhibit BMP signalling during embryonic axis formation (14). RSPO2 functions as BMP antagonist rather than WNT agonist also in acute myeloid leukemia (AML) cells, where RSPO2 promotes self-renewal (26). Moreover, in AML patients, elevated RSPO2 expression is a prognostic marker that strongly correlates with poor disease progression.…”