Genomic instability (GI) is essential for the initiation and evolution of many cancers and often precedes frank neoplastic conversion. Although GI can occur at several levels, the most conspicuous examples involve gains or losses of entire chromosomes (aneuploidy), the antecedent of which may be whole genome duplication (tetraploidy). Through largely undefined mechanisms, the c-Myc oncoprotein and its downstream target, MTMC1, promote tetraploidy and other forms of GI. In myeloid cells, c-Myc and MTMC1 also regulate a common, small subset of c-Myc target genes including GP1Balpha, which encodes a subunit of the von Willebrand's factor receptor complex that mediates platelet adhesion and aggregation. Gp1balpha also participates in megakaryocyte endomitosis, a form of controlled and precise whole-genome amplification. In this article, we show that both c-Myc and MTMC1 strongly up-regulate Gp1balpha concurrent with their promotion of tetraploidy. shRNA-mediated inhibition of Gp1balpha prevents tetraploidy by both c-Myc and MTMC1, whereas Gp1balpha overexpression alone is sufficient to induce tetraploidy in established and primary cells. Once acquired, tetraploidy persists in most cases examined. Our results indicate that chromosome-level GI, induced by c-Myc overexpression, proceeds by means of the sequential up-regulation of MTMC1 and Gp1balpha and further suggest that the pathways leading to megakaryocytic endomitosis and c-Myc-induced tetraploidy are mechanistically linked by their reliance on Gp1balpha.