Increased β4GALT1 expression associates with platelet surface galactosylation and thrombopoietin plasma levels in MPNs.

Aberrant megakaryopoiesis is a hallmark of the myeloproliferative neoplasms (MPNs), a group of clonal haematological malignancies originating from haematopoietic stem cells, leading to an increase in mature blood cells in the peripheral blood. Sialylated derivatives of the glycan structure β4-N-acetyllactosamine (Galβ1,4GlcNAc or type-2 LacNAc, thereafter referred to as LacNAc) regulate platelet lifespan, hepatic Thrombopoietin production, and thrombopoiesis. We found increased Thrombopoietin plasma levels in MPNs with high allele burden of the mutated clones. Remarkably, platelets isolated from MPNs had a significant increase in LacNAc expression that correlated with the high allele burden regardless of the underlying identified mutation. Megakaryocytes derived in vitro from these patients showed an increased expression of the B4GALT1 gene encoding β-1,4-galactosyltransferase1 (β4GalT1). Consistently, megakaryocytes from MPN showed increased LacNAc expression relative to healthy controls, which was counteracted by the treatment with a Janus Kinase 1/2 inhibitor. Altered expression of B4GALT1 in mutant megakaryocytes can lead to the production of platelets with aberrant galactosylation which in turn promote hepatic Thrombopoietin synthesis regardless of platelet mass. Our findings provide a new paradigm for understanding aberrant megakaryopoiesis in MPNs and identify β4GalT1 as a potential actionable target for therapy.