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Integrated Transcriptomic and Functional Analyses Reveal lncRNA-miRNA-mRNA Axis in AML Relapse After Allo-HSCT
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DOI：10.1111/cas.70417.png)
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Abstract
En 中文
Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the leading cause of treatment failure in acute myeloid leukemia (AML), yet the non-coding RNA-mediated regulatory mechanisms in relapse-driving tumor clones are not fully understood. In this study, we performed transcriptomic profiling of CD34+ cells from the bone marrow of patients who had relapsed after allo-HSCT and from those in sustained remission, and observed that long non-coding RNAs (lncRNAs) exhibited the largest magnitude of differential expression relative to other RNA classes. To systematically elucidate their function, we integrated correlation analysis, neighborhood topology, and thermodynamic modeling to construct relapse-associated competing endogenous RNA (ceRNA) networks. These networks highlighted multiple lncRNA-miRNA-mRNA axes potentially promoting leukemic progression. Functional interrogation using CRISPR-based xenograft assays and a single-cell CRISPR screening platform (Perturb-seq-like strategy) revealed that relapse-associated lncRNAs regulate AML cell proliferation and survival. Among them, SNHG8 emerged as a representative regulator that promotes relapse through the SNHG8-miR-625-ZC3H13/15 signaling axis. SNHG8 knockdown markedly impaired AML cell growth and triggered apoptosis. Furthermore, treatment with hypomethylating agents (HMAs) such as azacitidine and decitabine differentially modulated lncRNA/ceRNA expression signatures, thereby linking clinical interventions to transcriptomic regulation. Together, our findings identify lncRNA-ceRNA networks in post-transplant relapse of AML and identify the SNHG8 axis as a potential therapeutic vulnerability, providing a rationale for further investigation of lncRNA-targeted strategies in this clinical setting.
Keywords:
acute myeloid leukemia (AML)
allogeneic hematopoietic stem cell transplantation (Allo-HSCT) relapse
ceRNA networks
hypomethylating agents (HMA)
long non-coding RNA (lncRNA)
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