Stem Cell Biology, Developmental Leukemia and Immunotherapy Group, Josep Carreras Leukemia Research Institute, Barcelona, Spain.
GENYO, Centre for Genomics and Oncological Research, Pfizer/Universidad de Granada/Junta de Andalucía, Granada, Spain.
Blood. 2024 Nov 7;144(19):2002-2017. doi: 10.1182/blood.2023022050.
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, 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 in MLLr B-ALL. Despite its contribution to MLLr B-ALL pathogenesis, 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-ALF transcription elongation factor 4 (AF4) fusion protein. NG2 negatively regulates the expression of the GC receptor nuclear receptor subfamily 3 group C member 1 (NR3C1) and confers GC resistance to MLLr B-ALL cells. Mechanistically, NG2 interacts with FLT3 to render ligand-independent activation of FLT3 signaling (a hallmark of MLLr B-ALL) and downregulation of NR3C1 via activating protein-1 (AP-1)-mediated transrepression. 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.
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 基因重排的 B-ALL（也称为 KMT2A），称为 MLLr B-ALL，在婴儿中很常见，与 5 年生存率低、复发和对糖皮质激素 (GC) 的耐药性有关。GC 是 B-ALL 治疗的重要组成部分，GC 耐药性是预后不良的主要临床预测因素。因此，阐明 MLLr B-ALL 中 GC 耐药的机制对于指导治疗策略至关重要，这些策略可以在诱导治疗后加深反应。神经胶质抗原-2 (NG2) 的表达是 MLLr B-ALL 的一个标志，在健康造血细胞中表达很少。我们最近报道，NG2 表达与 MLLr B-ALL 的不良预后相关。尽管它对 MLLr B-ALL 的发病机制有贡献，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，我们表明 NG2 是白血病 MLL-ALF 转录延伸因子 4 (AF4) 融合蛋白的一种受表观遗传调控的直接靶基因。NG2 负调控 GC 受体核受体亚家族 3 组 C 成员 1 (NR3C1) 的表达，并赋予 MLLr B-ALL 细胞对 GC 的耐药性。在机制上，NG2 与 FLT3 相互作用，使 FLT3 信号转导无需配体激活（这是 MLLr B-ALL 的一个标志），并通过激活蛋白-1 (AP-1) 介导的转录抑制下调 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 中 GC 耐药中的作用，为 MLLr B-ALL 提供了新的治疗途径。
