Combining 5-azacitidine with the E-selectin antagonist uproleselan is an effective strategy to augment responses in myelodysplasia and acute myeloid leukaemia.

Autor: Enjeti AK; Calvary Mater Newcastle Hospital, Waratah, New South Wales, Australia.; NSW Health Pathology, John Hunter Hospital, New Lambton Heights, New South Wales, Australia.; Precision Medicine Program, Hunter Medical Research Institute and University of Newcastle, New Lambton Heights, New South Wales, Australia.; University of Newcastle, Callagan, NSW, Australia., Fogler WE; GlycoMimetics, Inc., Rockville, Maryland, USA., Smith TAG; GlycoMimetics, Inc., Rockville, Maryland, USA., Lincz LF; Calvary Mater Newcastle Hospital, Waratah, New South Wales, Australia.; University of Newcastle, Callagan, NSW, Australia., Bond DR; Precision Medicine Program, Hunter Medical Research Institute and University of Newcastle, New Lambton Heights, New South Wales, Australia.; University of Newcastle, Callagan, NSW, Australia., Magnani JL; GlycoMimetics, Inc., Rockville, Maryland, USA.
Jazyk: angličtina
Zdroj: British journal of haematology [Br J Haematol] 2024 Jun; Vol. 204 (6), pp. 2264-2274. Date of Electronic Publication: 2024 Apr 24.
DOI: 10.1111/bjh.19466
Abstrakt: The interaction of acute myeloid leukaemic (AML) blasts with the bone marrow (BM) microenvironment is a major determinant governing disease progression and resistance to treatment. The constitutive expression of E-selectin in the vascular compartment of BM, a key endothelial cell factor, directly mediates chemoresistance via E-selectin ligand/receptors. Despite the success of hypomethylating agent (HMA)-containing regimens to induce remissions in older AML patients, the development of primary or secondary resistance is common. We report that following treatment with 5-azacitidine, promoter regions regulating the biosynthesis of the E-selectin ligands, sialyl Lewis X, become further hypomethylated. The resultant upregulation of these gene products, in particular α(1,3)-fucosyltransferase VII (FUT7) and α(2,3)-sialyltransferase IV (ST3GAL4), likely causes functional E-selectin binding. When combined with the E-selectin antagonist uproleselan, the adhesion to E-selectin is reversed and the survival of mice transplanted with AML cells is prolonged. Finally, we present clinical evidence showing that BM myeloid cells from higher risk MDS and AML patients have the potential to bind E-selectin, and these cells are more abundant in 5-azacitidine-non-responsive patients. The collective data provide a strong rationale to evaluate 5-azacitidine in combination with the E-selectin antagonist, uproleselan, in this patient population.
(© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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