SummaryHuman induced pluripotent stem cells (iPSCs) provide a potentially replenishable source for the production of transfusable platelets. Here, we describe a method to generate megakaryocytes (MKs) and functional platelets from iPSCs in a scalable manner under serum/feeder-free conditions. The method also permits the cryopreservation of MK progenitors, enabling a rapid “surge” capacity when large numbers of platelets are needed. Ultrastructural/morphological analyses show no major differences between iPSC platelets and human blood platelets. iPSC platelets form aggregates, lamellipodia, and filopodia after activation and circulate in macrophage-depleted animals and incorporate into developing mouse thrombi in a manner identical to human platelets. By knocking out the β2-microglobulin gene, we have generated platelets that are negative for the major histocompatibility antigens. The scalable generation of HLA-ABC-negative platelets from a renewable cell source represents an important step toward generating universal platelets for transfusion as well as a potential strategy for the management of platelet refractoriness.

SUMMARY Oncogenic fusion proteins are capable of initiating tumorigenesis but the role of their wild-type counterparts in this process is poorly understood. The mixed lineage leukemia (MLL) gene undergoes chromosomal translocations, resulting in the formation of oncogenic MLL fusion proteins (MLL-FPs). Here we show that menin recruits both wild-type (wt) MLL and MLL-AF9 to the loci of Hox genes to activate their transcription. Wild-type MLL not only catalyzes histone methylation at key target genes but also controls distinct MLL-AF9-induced histone methylation. Notably, the wt Mll allele is required for MLL-AF9-induced leukemogenesis and maintenance of MLL-AF9-transformed cells. These findings suggest an essential cooperation between an oncogene and its wild-type counterpart in MLL-AF9-induced leukemogenesis.

The protein menin is encoded by the MEN1 gene, which is mutated in patients with multiple endocrine neoplasia type 1 (MEN1) syndrome. Although menin acts as a tumor suppressor in endocrine organs, it is required for leukemic transformation in mouse models. Menin possesses these dichotomous functions likely because it can both positively and negatively regulate gene expression as well as interact with a multitude of proteins with diverse functions. Here we review the recent progress in understanding the molecular mechanisms by which menin functions. The crystal structures of menin with different binding partners reveal that menin is a key scaffold protein that functionally crosstalks with various partners to regulate gene transcription and interplay with multiple signaling pathways.