异常的选择性剪接 (AS) 有助于白血病的发生，但有关异常的 AS 在急性髓系白血病 (AML) 中的临床和生物学影响的报道仍然有限。在这里，我们使用 RNA-seq 分析了 341 名患者的 AML 细胞中的 AS，并将它们与健康的 CD34 造血干细胞 (HSC) 进行比较。我们的研究结果强调了核转录因子 Y 亚基 α (NFYA) 基因中不同的 AS 模式，具有两种主要亚型：NFYA-L（长）和 NFYA-S（短），在外显子 3 包含方面有所不同。与 NFYA-L 较高但 NFYA 较低的患者相比，NFYA-L 较低但 NFYA-S 表达较高的患者（称为 NFYA-S 优势）在强化化疗后表现出更有利的特征和更好的结果，无论年龄和欧洲 LeukemiaNet 风险分类如何-S 表达，称为 NFYA-L 优势。使用癌症基因组图谱队列验证了预后效果。转录组分析显示，在 NFYA-S 主要病例中，细胞周期基因上调，与活跃的 HSC 类似，证明了相对的化学敏感性。相反，如在 KMT2A 重排白血病中观察到的，以 NFYA-L 为主的病例与相对化疗耐药相关。 OCI-AML3 细胞中 NFYA-S 过度表达促进细胞增殖、进入 S 期并增加阿糖胞苷敏感性，表明其在 AML 中的临床和治疗相关性。我们的研究强调 NFYA AS 作为 AML 的潜在预后生物标志物。© 2024 英国血液学会和 John Wiley

Aberrant alternative splicing (AS) contributes to leukemogenesis, but reports on the clinical and biological implications of aberrant AS in acute myeloid leukaemia (AML) remain limited. Here, we used RNA-seq to analyse AS in AML cells from 341 patients, comparing them to healthy CD34+ haematopoietic stem cells (HSCs). Our findings highlight distinct AS patterns in the nuclear transcription factor Y subunit alpha (NFYA) gene, with two main isoforms: NFYA-L (Long) and NFYA-S (Short), differing in exon 3 inclusion. Patients with lower NFYA-L but higher NFYA-S expression, termed NFYA-S predominance, displayed more favourable characteristics and better outcomes following intensive chemotherapy, regardless of age and European LeukemiaNet risk classification, compared to those with higher NFYA-L but lower NFYA-S expression, termed NFYA-L predominance. The prognostic effects were validated using The Cancer Genome Atlas cohort. Transcriptome analysis revealed upregulated cell cycle genes in NFYA-S predominant cases, resembling those of active HSCs, demonstrating relative chemosensitivity. Conversely, NFYA-L predominant cases, as observed in KMT2A-rearranged leukaemia, were associated with relative chemoresistance. NFYA-S overexpression in OCI-AML3 cells promoted cell proliferation, S-phase entry and increased cytarabine sensitivity, suggesting its clinical and therapeutic relevance in AML. Our study underscores NFYA AS as a potential prognostic biomarker in AML.© 2024 British Society for Haematology and John Wiley & Sons Ltd.