Inhibitory Receptors Act in Stem Cell Maintenance and Leukemia Development

Despite their key roles in hematopoietic stem cell (HSC) expansion, angiogenesis, inflammation, and lipid metabolism, the 7 secreted glycoproteins that make up the angiopoietin-like protein (ANGPTL) family are considered orphan ligands with no known receptors. Zheng and colleagues ectopically expressed cell surface receptors and used flow cytometry to screen for those that bound glutathione S-transferase–labeled ANGPTLs. Unexpectedly, leukocyte immunoglobulin-like receptor B2 (LILRB2), an inhibitory receptor that suppresses inappropriate immune responses, bound ANGPTL2 and ANGPTL5 with high affinity. Because several ANGPTLs had previously been linked to HSC expansion, the authors evaluated LILRB2 expression on human HSCs and found that LILRB2 was expressed on the majority of HSC-enriched human cord blood cells. Loss of LILRB2 or its mouse ortholog, paired Ig-like receptor B (PIRB), which also bound ANGPTLs and was expressed on HSCs, decreased ANGPTL binding and the repopulation of HSCs, indicating that ANGPTL-dependent HSC expansion is mediated by LILRB2/PIRB. Mechanistically, ANGPTL5 binding induced nonreceptor type 11 (PTPN11/SHP2) recruitment and activation of calcium/calmodulin-dependent protein kinase 4 (CAMK4), both of which are required for HSC repopulation. Of note, LILRB2 is highly expressed in human acute monoblastic and monocytic leukemia, a subtype of acute myeloid leukemia (AML) associated with mixed-lineage leukemia (MLL) translocations. Consistent with a potential role for LILRB2 in the development of AML, the onset of AML was delayed in mice transplanted with MLL–AF9– or AML1–ETO–expressing hematopoietic progenitors lacking functional PIRB. In vitro, PIRB expression was required to suppress differentiation and promote self-renewal of AML cells. Together, these results implicate LILRB2 as an ANGPTL receptor and link immune-inhibitory receptors to the maintenance of stem cell and cancer cell populations.

Zheng J, Umikawa M, Cui C, Li J, Chen X, Zhang C, et al. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 2012;485:656–60.