Megakaryocytes, the rare platelet-producing cells within the bone marrow, undergo an unusual developmental transition from early mitotic proliferation to endomitosis associated with polyploidization and enlargement. This transition is precisely coordinated with a lineage-specific differentiation program and equips the cell with sufficient mass to yield proplatelet extensions that shed appropriate numbers of platelets into the circulation. While the mechanisms that maintain this choreography remain obscure, the disastrous consequences of even slight miscues are evident in several diseases. A common feature of human myeloproliferative neoplasms (MPNs), for example, consists of enhanced mitotic proliferation resulting in excessive and malformed megakaryocytes. In this issue, Ye et al. broaden our understanding of megakaryopoietic regulation with a new signaling pathway whose perturbation elicits MPN-like features.

While characterizing mutant mice deficient in cytosolic carboxypeptidase (CCP) 6, the authors documented a selective increase in platelet counts, which resulted from a ∼threefold increase in megakaryocytes in marrow and in spleen. Paradoxically, the animals had prolonged bleeding times due to defective platelet aggregation. CCP6-deficient megakaryocytes displayed enhanced mitotic proliferation and decreased endomitosis, leading to impaired polyploidization and enlargement. In humans, elevated platelets with defective aggregation combined with increased marrow megakaryocytes occur in the MPNs essential thrombocythemia (ET) and chronic myelogenous leukemia (CML), and defective megakaryocytic polyploidization occurs in CML.

Starting with the known function of CCP6 in removal of polyglutamate protein modifications, the authors pieced together an entirely new megakaryopoietic regulatory cascade. Specifically, loss of CCP6 increased polyglutamylation of the spindle checkpoint protein MAD2. This MAD2 modification promoted recruitment and hyperactivation of the mitotic kinase Aurora B, which is normally inhibited by MAD2. A series of elegant rescue experiments confirmed the functional significance of each step. Thus, normal megakaryopoiesis could be restored in CCP6-deficient progenitors through either knockdown of the relevant polyglutamylase TTLL6, replacement of wild-type MAD2 with a glutamylation-acceptor mutant, or inhibition of Aurora kinase activity.

Inappropriate Aurora kinase activity likely contributes to polyploidization defects in human megakaryocytic neoplasms and represents an attractive therapeutic target. How polyglutamate modification converts MAD2 from inhibitor to activator of Aurora B remains an intriguing question with potential clinical relevance. Furthermore, this paper raises the possibility that perturbations in megakaryocytic MAD2 glutamylation, normally maintained by the balance of TTLL6 and CCP6 activities, could contribute to human MPN. Future topics of interest include the influence MPN signaling defects—e.g., JAK2 V617F—on MAD2 glutamylation and the potential role of Aurora inhibitors in MPN therapy.

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J. Exp. Med.