Bakhtiari Mojtaba, Jordan Sean C, Mumme Hope L, Sharma Richa, Shanmugam Mala, Bhasin Swati S, Bhasin Manoj
Aflac Cancer and Blood Disorders Center, Children Healthcare of Atlanta, Atlanta, GA, United States.
Department of Biomedical Informatics, Emory University, Atlanta, GA, United States.
Front Oncol. 2024 Dec 5;14:1445173. doi: 10.3389/fonc.2024.1445173. eCollection 2024.
Despite remarkable progress in Pediatric Acute Myeloid Leukemia (pAML) treatments, the relapsed disease remains difficult to treat, making it pertinent to identify novel biomarkers of prognostic/therapeutic significance.
Bone marrow samples from 21 pAML patients were analyzed using single cell RNA sequencing, functional assays with knockdown and overexpression were performed in leukemia cell lines to evaluate impact on proliferation and migration, and chemotherapy sensitivity. Mitochondrial function was assessed via Seahorse assay, interacting proteins were studied using co-immunoprecipitation. Bulk RNA-seq was performed on knockdown and over expressing cell lines to evaluate the pathways and networks impacted by .
Our data shows that , a novel cancer-associated gene, is highly expressed in the malignant blast cells of multiple pediatric hematologic malignancies, including AML, T/B-ALL, and T/B-MPAL. Notably, expression is significantly elevated in blast cells of patients who relapsed or have a high-risk cytogenetic profile (MLL) compared to standard-risk (). expression is also significantly correlated with the pediatric leukemia stem cell score of 6 genes (LSC6) associated with poor outcomes. Perturbation of (knockdown and overexpression) in leukemia cell lines significantly impacted cell proliferation and migration. The RNA-sequencing analysis on multiple knockdown and overexpressing cell lines established an association with mitochondrial fatty acid synthesis and cell cycle pathways.The investigation of the mitochondrial matrix shows that pharmacological inhibition of a key enzyme in fatty acid synthesis regulation, , resulted in downregulation. knockdown also led to a significant reduction in and ATP production as well as Oxygen Consumption Rate. Our data indicates that downregulating impacts cell proliferation by reducing key cell cycle regulators such as and . Further, we also established that is a key physical interactant of , associated with multiple cancers.
Our findings underscore further evaluation of as a potential candidate for targeted therapies and stratification of aggressive pAML to improve outcomes.
尽管小儿急性髓系白血病（pAML）治疗取得了显著进展，但复发疾病仍难以治疗，因此确定具有预后/治疗意义的新型生物标志物至关重要。
使用单细胞RNA测序分析了21例pAML患者的骨髓样本，在白血病细胞系中进行了基因敲低和过表达的功能试验，以评估对增殖、迁移和化疗敏感性的影响。通过海马分析评估线粒体功能，使用免疫共沉淀研究相互作用蛋白。对基因敲低和过表达的细胞系进行批量RNA测序，以评估受影响的途径和网络。
我们的数据表明，一种新型癌症相关基因在多种小儿血液系统恶性肿瘤的恶性原始细胞中高表达，包括AML、T/B-ALL和T/B-MPAL。值得注意的是，与标准风险患者相比，复发或具有高危细胞遗传学特征（MLL）的患者原始细胞中该基因的表达显著升高。该基因的表达也与6个与不良预后相关的基因（LSC6）的小儿白血病干细胞评分显著相关。白血病细胞系中该基因的干扰（敲低和过表达）显著影响细胞增殖和迁移。对多个该基因敲低和过表达细胞系的RNA测序分析建立了与线粒体脂肪酸合成和细胞周期途径的关联。对线粒体基质的研究表明，脂肪酸合成调节关键酶的药理学抑制导致该基因下调。该基因敲低还导致该基因和ATP产生以及氧消耗率显著降低。我们的数据表明，下调该基因通过减少关键细胞周期调节因子如某物质和某物质来影响细胞增殖。此外，我们还确定该基因是某物质的关键物理相互作用分子，与多种癌症相关。
我们的研究结果强调进一步评估该基因作为靶向治疗的潜在候选物以及对侵袭性pAML进行分层以改善预后的重要性。
