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An alternative transcription factor isoform controls AML chemoresistance [LongRead_mRNA]

ABSTRACT: Aberrant splicing is a hallmark of many cancers, including Acute Myeloid Leukemia (AML), but its role in post-treatment relapse remains poorly understood. Here, we analyzed the alternative splicing landscape of 19 AML patients during chemotherapy treatment. We found an upregulation of the long isoform of the transcription factor RUNX1 (also known as RUNX1C) in relapsed cohorts, which conferred chemotherapy resistance. Notably, these patients showed elevanted intragenic DNA methylation at the RUNX1 proximal promoter, thereby activating RUNX1C transcript through its alternative distal promoter. Mechanistically the N-terminus region of RUNX1C is required to promote chemoresistance by regulating a distinct RUNX1 transciptional program. Among these target genes, B-cell translocation gene 2 (BTG2) mediates a quiescent-like phenotype by deadenylating ribosomal RNAs to reduce global protein synthesis. Lastly, we harnessed orthogonal RNA-targeting strategies to target RUNX1C isoform, which led to augmented chemotherapy efficacy. Collectively, our finidngs delineate a transcriptional circuity orchestrated by a transcription factor isoform that underpins chemotherapy responsiveness and a potential therapeutic strategy to mitigate disease recurrence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273359 | GEO | 2025/05/29

REPOSITORIES: GEO

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Project description:PURPOSE: To evaluate frequency, biological features and clinical relevance of RUNX1 mutations in acute myeloid leukemia (AML). PATIENTS AND METHODS: Diagnostic samples from 945 patients (18 to 60 years) were analyzed for RUNX1 mutations. In a subset of cases (n=269) microarray gene expression analysis was performed. RESULTS: Fifty-nine RUNX1 mutations were identified in 53 of 945 (5.6%) cases, predominantly in exons 3 (n=11), 4 (n=10) and 8 (n=23). RUNX1 mutations clustered in the intermediate-risk cytogenetic group (46/640, 7.2%; cytogenetically normal, 34/538, 6.3%), they were less frequent in adverse-risk cytogenetics (5/109, 4.6%), and absent in core-binding-factor AML (0/77) and acute promyelocytic leukemia (0/61); RUNX1 mutations were associated with MLL-partial tandem duplications (p=0.0007) and IDH1/IDH2 mutations (p=0.03), inversely correlated with NPM1 (p<0.0001) and in trend with CEBPA (p=0.10) mutations. RUNX1 mutations were characterized by a distinct gene expression pattern; this RUNX1 mutation-derived signature was not exclusive for the mutation, but also included mostly adverse-risk AML [eg, 7q-, -7, inv(3) or t(3;3)]. RUNX1 mutations predicted for resistance to chemotherapy (rates of refractory disease 30% and 19%, p=0.047, for RUNX1-mutated and wildtype patients, respectively), as well as inferior event-free survival (EFS; p<0.0001), relapse-free survival (RFS, p=0.022), and overall survival (p=0.051). In multivariable analysis, RUNX1 mutations were an independent prognostic marker for shorter EFS (p=0.007). Explorative subgroup analysis revealed that allogeneic hematopoietic stem cell transplantation had a favorable impact on RFS in RUNX1-mutated patients (p<0.0001). CONCLUSION: AML with RUNX1 mutations exhibit distinct biological properties and are associated with resistance to therapy and inferior outcome. A total of 269 RNA samples derived from adult AML patients were provided by the German Austrian AML Study Group (AMLSG) [AMLSG trial AML HD98A (ClinicalTrials.gov Identifier: NCT00146120)]. Conventional cytogenetic banding, and FLT3, CEBPA and NPM1 mutational analysis were performed as previously described (Schlenk et al., N Engl J Med 2008). Detailed clinical, cytogenetic and molecular cytogenetic information are also provided in the supplementary information. Following enrichment, all samples contained at least 80% leukemic cells. Gene expression profiling (GEP) was performed as previously described (Bullinger et al., N Engl J Med 2004).

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An alternative transcription factor isoform controls AML chemoresistance [LongRead_mRNA]

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