Clinical relevance of NFYA splice variants in patients with acute myeloid leukaemia undergoing intensive chemotherapy

• Published in: British journal of haematology Vol. 205; no. 5; pp. 1751 - 1764
• Main Authors: Yang, Yi‐Tsung, Yao, Chi‐Yuan, Kao, Chein‐Jun, Chiu, Po‐Ju, Lin, Ming‐En, Hou, Hsin‐An, Lin, Chien‐Chin, Chou, Wen‐Chien, Tien, Hwei‐Fang
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-11-2024
• Subjects: acute myeloid leukaemia; Acute myeloid leukemia; Alternative splicing; CD34 antigen; Cell cycle; Cell proliferation; Chemoresistance; Chemotherapy; clinical significance; Cytarabine; Genomic analysis; Hematopoietic stem cells; Isoforms; Leukemia; Leukemogenesis; NFYA; RNA sequencing; Transcriptomes; RNA sequencing; NFYA; alternative splicing; clinical significance; acute myeloid leukaemia
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/bjh.19733

Summary
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.
The NFYA gene has two main isoforms: NFYA‐L (Long) and NFYA‐S (Short), which differ in their inclusion of exon 3. In clinical practice, AML can be categorized into four groups based on NFYA isoform expression: NFYA‐L low/NFYA‐S high, NFYA‐L high/NFYA‐S high, NFYA‐L low/NFYA‐S low and NFYA‐L high/NFYA‐S low. NFYA splicing patterns significantly affect outcomes for AML patients following intensive chemotherapy, particularly in distinguishing between the NFYA‐L low/NFYA‐S high and NFYA‐L high/NFYA‐S low groups.