Running Title: Developmental differences in megakaryocytopoiesis DEVELOPMENTAL DIFFERENCES IN MEGAKARYOCYTOPOIESIS ARE ASSOCIATED WITH UP-REGULATED TPO SIGNALING THROUGH mTOR AND ELEVATED GATA-1 LEVELS IN NEONATAL MEGAKARYOCYTES

Multiple observations support the existence of developmental differences in megakaryocytopoiesis. We have previously shown that neonatal MK progenitors are hyperproliferative, and give rise to MKs smaller and of lower ploidy than adult MKs. Based on these characteristics, neonatal MKs have been considered immature. The molecular mechanisms underlying these differences are unclear, but contribute to the pathogenesis of disorders of neonatal megakaryocytopoiesis. Here we demonstrate that low-ploidy neonatal MKs, contrary to traditional belief, are more mature than adult low-ploidy MKs. These mature MKs are generated at a 10-fold higher rate than adult MKs, and result from a developmental uncoupling of proliferation, polyploidization, and terminal differentiation. This pattern is associated with upregulated TPO signaling through mTOR and elevated levels of full length GATA-1 and its targets. Blocking of mTOR with rapamycin suppressed the maturation of neonatal MKs without affecting ploidy, in contrast to the synchronous inhibition of polyploidization and cytoplasmic maturation in adult MKs. We propose that these mechanisms allow fetuses/neonates to populate their rapidly expanding bone marrow and intravascular spaces while maintaining normal platelet counts, but also set the stage for disorders restricted to fetal/neonatal MK progenitors, including Down syndrome-transient myeloproliferative disorder and the severe thrombocytopenia of TAR syndrome. For personal use only. on May 1, 2017. by guest www.bloodjournal.org From