Increased B4GALT1 expression is associated with platelet surface galactosylation and thrombopoietin plasma levels in MPNs. Blood 2021 Apr 15;137(15):2085-2089
Date
11/26/2020Pubmed ID
33238000Pubmed Central ID
PMC8057261DOI
10.1182/blood.2020007265Scopus ID
2-s2.0-85102992612 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
Aberrant megakaryopoiesis is a hallmark of the myeloproliferative neoplasms (MPNs), a group of clonal hematological malignancies originating from hematopoietic 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, hereafter referred to as LacNAc) regulate platelet life span, hepatic thrombopoietin (TPO) production, and thrombopoiesis. We found increased TPO 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-galactosyltransferase 1 (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 TPO 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.
Author List
Di Buduo CA, Giannini S, Abbonante V, Rosti V, Hoffmeister KM, Balduini AAuthor
Karin Hoffmeister MD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Blood PlateletsGalactose
Galactosyltransferases
Humans
Megakaryocytes
Mutation
Myeloproliferative Disorders
Thrombopoietin
Up-Regulation
