靶向治疗的发展为患有无法治愈的癌症的患者带来了新的希望。然而，仍然存在多种挑战，特别是在控制难治性和转移性疾病患者的肿瘤细胞可塑性方面。神经母细胞瘤（NB）是一种侵袭性儿科恶性肿瘤，起源于神经嵴衍生祖细胞的分化缺陷，由于遗传和表观遗传改变而具有致癌活性，对于高危患者来说仍然是一个临床挑战。为了确定驱动 NB 侵袭性的关键基因，我们对匹配的患者来源的异种移植物 (PDX)、球体和源自转移性 MYCN 非扩增肿瘤的分化贴壁培养物进行了染色质和转录组组合分析。 X 染色体上的骨髓激酶 (BMX) 被认为是 PDX 和球体与贴壁模型中差异最大的调节基因之一。 BMX 表达与高肿瘤分期和较差的患者生存率相关，并且对于维持 NB 球体的自我更新和致瘤潜力至关重要。此外，BMX 表达与间充质 NB 细胞表型呈正相关，此前与化疗耐药性增加相关。最后，BMX 抑制剂很容易逆转这种细胞状态，增加 NB 球体对化疗的敏感性，并部分减少临床前 NB 模型中的肿瘤生长。总而言之，我们的研究确定 BMX 是高危 MYCN 非扩增 NB 患者的一个有前途的创新治疗靶点。

The development of targeted therapies offers new hope for patients affected by incurable cancer. However, multiple challenges persist, notably in controlling tumor cell plasticity in patients with refractory and metastatic illness. Neuroblastoma (NB) is an aggressive pediatric malignancy originating from defective differentiation of neural crest-derived progenitors with oncogenic activity due to genetic and epigenetic alterations and remains a clinical challenge for high-risk patients. To identify critical genes driving NB aggressiveness, we performed combined chromatin and transcriptome analyses on matched patient-derived xenografts (PDXs), spheroids, and differentiated adherent cultures derived from metastatic MYCN nonamplified tumors. Bone marrow kinase on chromosome X (BMX) was identified among the most differentially regulated genes in PDXs and spheroids versus adherent models. BMX expression correlated with high tumor stage and poor patient survival and was crucial to the maintenance of the self-renewal and tumorigenic potential of NB spheroids. Moreover, BMX expression positively correlated with the mesenchymal NB cell phenotype, previously associated with increased chemoresistance. Finally, BMX inhibitors readily reversed this cellular state, increased the sensitivity of NB spheroids toward chemotherapy, and partially reduced tumor growth in a preclinical NB model. Altogether, our study identifies BMX as a promising innovative therapeutic target for patients with high-risk MYCN nonamplified NB.