Abstract：
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.
摘要：
急性骨髓性白血病（AML）母细胞与骨髓（BM）微环境的相互作用是控制疾病进展和对治疗的抵抗力的主要决定因素。E-选择素在BM血管区室的组成型表达,一个关键的内皮细胞因子，通过E-选择素配体/受体直接介导化学抗性。尽管含低甲基化药物（HMA）的方案在老年AML患者中成功诱导缓解，初级或次级抗药性的发展是常见的。我们报告说，在用5-阿扎胞苷治疗后，启动子区域调节E-选择素配体的生物合成，唾液酸LewisX,变得进一步低甲基化。这些基因产物的上调，特别是α（1,3）-岩藻糖基转移酶VII（FUT7）和α（2,3）-唾液酸转移酶IV（ST3GAL4），可能导致功能性E-选择素结合。当与E-选择素拮抗剂uproleselan联合使用时，与E-选择素的粘附被逆转,并且移植有AML细胞的小鼠的存活被延长。最后,我们提供的临床证据表明，来自高危MDS和AML患者的BM骨髓细胞具有结合E-选择素的潜力，这些细胞在5-阿扎胞苷无反应的患者中更丰富。集体数据为评估5-阿扎胞苷与E-选择素拮抗剂的组合提供了强有力的理由。uproleselan,在这个患者群体中。
