Methionine aminopeptidase 2 is required for hematopoietic stem cell initiation and proliferation

In a chemical screening, we tested the anti-angiogenic effects of fumagillin derivatives and identified fumagillin as an inhibitor of definitive hematopoiesis in zebrafish embryos. Fumagillin is known to target methionine aminopeptidase II (MetAP2), an enzyme whose function in hematopoiesis is unknown. We investigated the role of MetAP2 in hematopoiesis using zebrafish embryo and human umbilical cord blood (CB) models. Zebrafish metap2 expressed ubiquitously during early embryogenesis and later in the somitic region, the caudal hematopoietic tissue and pronephric duct. metap2 was inhibited by morpholino (MO) and fumagillin treatment, resulting in increased mpo expression at 18 hour-post-fertilization (hpf) and reduced c-myb expression along the ventral wall of dorsal aorta at 36 hpf. It also disrupted inter-segmental vessels in Tg(fli1:gfp) embryos without affecting development of major axial vasculatures. Inhibition of MetAP2 in CB CD34+ cells by fumagillin had no effect on overall clonogenic activity but significantly reduced their engraftment into NOD/SCID mice. metap2 knock-down in zebrafish and inhibition by fumagillin in zebrafish and human CB CD34+ cells inhibited calmodulin Kinase II (CamKII) activity and induced ERK phosphorylation. This study demonstrated a hitherto undescribed role of MetAP2 in definitive hematopoiesis and a possible link to non-canonical Wnt and ERK signaling.