Understanding causality and impact of ancestry-specific expression of long non-coding RNAs in acute myeloid leukemia patients
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Date
2025-05
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The Ohio State University
Abstract
Background: African American AML patients, referred to as Black pts, have shorter survival than pts of European ancestry, referred to as White pts. However, our information about the non-coding expression profile and associated clinical relevance of long non-coding RNA (lncRNA) in AML stems from studies based on White pts. Single nucleotide polymorphisms (SNPs) in promoter regions of lncRNA sequences affect gene regulation. We hypothesize that ancestry-associated mutations in SNPs involved in lncRNA expression may be contributing to disparities in survival.
Methods: We analyzed 681 adult AML pts treated on CALBG/Alliance frontline protocols (n=616 White pts, n=65 Black pts; ancestries self-identified and genotype confirmed.) All pts had ribo-depleted, paired-end 151bp RNA sequencing (60-80 million reads/sample), comprehensive gene mutation profiling (80 gene panel), clinical annotations and long-term follow-up data to determine differential lncRNA expression. A negative binomial model was fit to identify lncRNA differential expression between Black and White pts. Ancestry-associated SNPs in regulatory regions of select lncRNAs were identified using the ENCODE registry for cCREs, SNP2TFBS and population allele frequency data from NCBI ALFA.
Results: Comparing Black and White AML pts, 135 lncRNAs were upregulated and 55 were downregulated. The differentially expressed lncRNAs were equally distributed throughout the genome and none were ancestry-exclusive, indicated high conservation. 190 aberrantly expressed lncRNA were identified and used to derive a prognostic lncRNA score consisting of 13 lncRNAs. lncRNA score was an independent indicator of inferior survival in both Black and White pts that refined the prognostication of the European LeukemiaNet 2022 Favorable (P=.004) and Intermediate (P<.001) genetic risk groups. Examination of the genomic context of regulatory regions within the 13 lncRNAs revealed multiple ancestry-associated SNPs that putatively altered transcription factor (TF)/chromatin regulator binding sites in cis-regulatory regions, including rs58515841 (MAF white vs Black, 24% vs 9%, CTCF binding site within ENSG00000284052) and rs1400262 (MAF, 62% vs 10%, REST binding site upstream of NCK1-DT). To validate differential TF binding, we are performing electrophoretic mobility shift assays of candidate lnc TF binding sites.
Conclusion: We depict an ancestry-inclusive landscape of lncRNAs in AML through the expression profile of lncRNAs and SNPs as modulators, all ancestry-associated
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Keywords
Ancestry, Acute Myeloid Leukemia (AML), Long non-coding RNA (lncRNA), AML prognosis