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

Acute myeloid leukemia (AML) is a rapidly progressing cancer, for which chemotherapy remains standard treatment and additional therapeutic targets are requisite. Here, we show that AML cells secrete the stem cell growth factor R-spondin 2 (RSPO2) to promote their self-renewal and prevent cell differentiation. Although RSPO2 is a well-known WNT agonist, we reveal that it maintains AML self-renewal WNT independently, by inhibiting BMP receptor signaling. Autocrine RSPO2 signaling is also required to prevent differentiation and to promote self-renewal in normal hematopoietic stem cells as well as primary AML cells. Comprehensive datamining reveals that RSPO2 expression is elevated in patients with AML of poor prognosis. Consistently, inhibiting RSPO2 prolongs survival in AML mouse xenograft models. Our study indicates that in AML, RSPO2 acts as an autocrine BMP antagonist to promote cancer cell renewal and may serve as a marker for poor prognosis. [Display omitted] •RSPO2 is a regulator of AML cell self-renewal•RSPO2 acts as a BMP antagonist instead of as a WNT agonist in AML•High RSPO2 expression is a marker for adverse prognosis in AML Sun et al. report that the secreted stem cell growth factor R-spondin 2 (RSPO2) acts as a BMP signaling antagonist to promote self-renewal in acute myeloid leukemia cells. High RSPO2 expression predicts poor prognosis, suggesting RSPO2 as potential prognostic marker and drug target in AML.