B 细胞急性淋巴细胞白血病 (B-ALL) 是最常见的儿科癌症，长期总生存率约为 85%。然而，携带 MLL 基因重排（也称为 KMT2A）的 B-ALL（称为 MLLr B-ALL）在婴儿中很常见，并且与 5 年生存率较差（<30%）、频繁复发和难治性相关糖皮质激素（GC）。 GC 是 B-ALL 治疗支柱的重要组成部分，GC 耐药是预后不良的主要临床预测因素。因此，阐明 MLLr B-ALL 的 GC 耐药机制对于指导深化诱导治疗后反应的治疗策略至关重要。神经胶质抗原 2 (NG2) 表达是 MLLr B-ALL 的标志，在健康造血细胞中表达量最低。我们最近报道，NG2 表达与不良预后相关，并且抗 NG2 免疫疗法可显着减少/延迟 MLLr B-ALL 异种移植模型的复发。尽管NG2对MLLr B-ALL发病机制及其诊断用途有贡献，但NG2在MLLr介导的白血病发生/化疗耐药中的作用仍然难以捉摸。在这里，我们证明NG2是白血病MLL-AF4融合蛋白的表观遗传调控的直接靶基因。 NG2 负调节 GC 受体 NR3C1 的表达，并在体外和体内赋予 MLLr B-ALL 细胞 GC 抗性。从机制上讲，NG2 与 FLT3 相互作用，使 FLT3 信号传导（MLLr B-ALL 的标志）不依赖于配体激活，并通过 AP-1 介导的反式抑制下调 NR3C1。总的来说，我们的研究通过 FLT3/AP-1 介导的 NR3C1 下调阐明了 NG2 在 MLLr B-ALL GC 耐药中的作用，为 MLLr B-ALL 提供了新的治疗途径。版权所有 © 2024 美国血液学会。

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, with long-term overall survival rates of ~85%. However, B-ALL harboring rearrangements of the MLL gene (also known as KMT2A), referred to as MLLr B-ALL, is common in infants and is associated with poor 5-year survival (<30%), frequent relapses, and refractoriness to glucocorticoids (GCs). GCs are an essential part of the treatment backbone for B-ALL and GC resistance is a major clinical predictor of poor outcome. Elucidating the mechanisms of GC resistance in MLLr B-ALL is, therefore, critical to guide therapeutic strategies that deepen the response after induction therapy. Neuron-glial antigen-2 (NG2) expression is a hallmark of MLLr B-ALL and is minimally expressed in healthy hematopoietic cells. We recently reported that NG2 expression is associated with poor prognosis and that anti-NG2 immunotherapy strongly reduces/delays relapse in MLLr B-ALL xenograft models. Despite its contribution to MLLr B-ALL pathogenesis and its diagnostic utility, the role of NG2 in MLLr-mediated leukemogenesis/chemoresistance remains elusive. Here we show that NG2 is an epigenetically regulated direct target gene of the leukemic MLL-AF4 fusion protein. NG2 negatively regulates the expression of the GC receptor NR3C1 and confers GC resistance to MLLr B-ALL cells in vitro and in vivo. Mechanistically, NG2 interacts with FLT3 to render ligand-independent activation of FLT3 signaling (a hallmark of MLLr B-ALL) and downregulation of NR3C1 via AP-1-mediated trans-repression. Collectively, our study elucidates the role of NG2 in GC resistance in MLLr B-ALL through FLT3/AP-1-mediated downregulation of NR3C1, providing novel therapeutic avenues for MLLr B-ALL.Copyright © 2024 American Society of Hematology.