Evaluation of the clinical significance of global <scp>mRNA</scp> alternative splicing in patients with acute myeloid leukemia

Yang, Yi; Yao, Chi‐Yuan; Chiu, Po-Ju; Kao, Chein-Jun; Hou, Hsin‐An; Lin, Chien‐Chin; Chou, Wen‐Chien; Tien, Hwei‐Fang

doi:10.1002/ajh.26893

Cited by 3 publications

(1 citation statement)

References 43 publications

(101 reference statements)

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“…293 Given the important role of AS in AML, associating the global effects of AS on AML with prognosis is quite significant. Through analyzing AML patients in the National Taiwan University Hospital (NTUH) cohort and the TCGA database, ASEs of SYTL4, MYO9B, GFI1, and NPIPB4 are confirmed with independent prognostic significance, 294 which greatly promotes the exploration of global ASEs in tumors and provides new ideas for risk stratification of patients. Wang et al 295 utilized CRISPR-Cas9 screening to discover that the combined application of BCL2 inhibitors and RBM10 inhibitors can result in the inactivation of the apoptosis inhibitor XIAP.…”

Section: Acute Myeloid Leukemia (Aml)mentioning

confidence: 99%

Alternative splicing and related RNA binding proteins in human health and disease

Tao,

Zhang,

Wang

et al. 2024

Sig Transduct Target Ther

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Alternative splicing (AS) serves as a pivotal mechanism in transcriptional regulation, engendering transcript diversity, and modifications in protein structure and functionality. Across varying tissues, developmental stages, or under specific conditions, AS gives rise to distinct splice isoforms. This implies that these isoforms possess unique temporal and spatial roles, thereby associating AS with standard biological activities and diseases. Among these, AS-related RNA-binding proteins (RBPs) play an instrumental role in regulating alternative splicing events. Under physiological conditions, the diversity of proteins mediated by AS influences the structure, function, interaction, and localization of proteins, thereby participating in the differentiation and development of an array of tissues and organs. Under pathological conditions, alterations in AS are linked with various diseases, particularly cancer. These changes can lead to modifications in gene splicing patterns, culminating in changes or loss of protein functionality. For instance, in cancer, abnormalities in AS and RBPs may result in aberrant expression of cancer-associated genes, thereby promoting the onset and progression of tumors. AS and RBPs are also associated with numerous neurodegenerative diseases and autoimmune diseases. Consequently, the study of AS across different tissues holds significant value. This review provides a detailed account of the recent advancements in the study of alternative splicing and AS-related RNA-binding proteins in tissue development and diseases, which aids in deepening the understanding of gene expression complexity and offers new insights and methodologies for precision medicine.

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Section: Acute Myeloid Leukemia (Aml)mentioning

confidence: 99%

Alternative splicing and related RNA binding proteins in human health and disease

Tao,

Zhang,

Wang

et al. 2024

Sig Transduct Target Ther

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

Yang,

Yao,

Kao

et al. 2024

Br J Haematol

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SummaryAberrant 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.

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The Proteasome-Family-Members-Based Prognostic Model Improves the Risk Classification for Adult Acute Myeloid Leukemia

Sheng,

Tao,

Jin

et al. 2024

Biomedicines

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Background: The accumulation of diverse molecular and cytogenetic variations contributes to the heterogeneity of acute myeloid leukemia (AML), a cluster of hematologic malignancies that necessitates enhanced risk evaluation for prognostic prediction and therapeutic guidance. The ubiquitin–proteasome system plays a crucial role in AML; however, the specific contributions of 49 core proteasome family members (PSMs) in this context remain largely unexplored. Methods: The expression and survival significance of 49 PSMs in AML were evaluated using the data from BeatAML2.0, TCGA, and the GEO database, mainly through the K-M plots, differential genes enrichment analysis, and candidate compounds screening via R language and statistical software. Results: we employed LASSO and Cox regression analyses and developed a model comprising three PSMs (PSMB8, PSMG1, and PSMG4) aimed at predicting OS in adult AML patients, utilizing expression profiles from the BeatAML2.0 training datasets. Patients with higher risk scores were predominantly found in the AML–M2 subtype, exhibited poorer ELN stratification, showed no complete remission following induction therapies, and had a higher mortality status. Consistently, significantly worse OS was observed in high-risk patients across both the training and three validation datasets, underscoring the robust predictive capability of the three-PSMs model for AML outcomes. This model elucidated the distinct genetic abnormalities landscape between high- and low-risk groups and enhanced the ELN risk stratification system. Ultimately, the three-PSMs risk score captured AML-specific gene expression signatures, providing a molecular basis for selecting potential therapeutic agents. Conclusions: In summary, these findings manifested the significant potential of the PSM model for predicting AML survival and informed treatment strategies.

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Evaluation of the clinical significance of global mRNA alternative splicing in patients with acute myeloid leukemia

Cited by 3 publications

References 43 publications

Alternative splicing and related RNA binding proteins in human health and disease

Alternative splicing and related RNA binding proteins in human health and disease

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

The Proteasome-Family-Members-Based Prognostic Model Improves the Risk Classification for Adult Acute Myeloid Leukemia

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