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Long non-coding RNA H19 is overexpressed in azacitidine-resistant K562 cells but does not modulate drug sensitivity [smallRNA-Seq]

ABSTRACT: Resistance to azacitidine represents a major obstacle in the treatment of acute myeloid leukemia (AML), yet the molecular mechanisms remain poorly understood. Long non-coding RNAs (lncRNAs) have been implicated in drug resistance across cancers, with H19 emerging as a promising candidate due to its oncogenic roles and association with adverse outcomes in AML. Here, we investigated whether H19 contributes to azacitidine resistance. Using K562 cells subjected to prolonged drug exposure, we established an azacitidine-resistant model that maintained proliferation and viability and resisted apoptosis under treatment. RNA sequencing revealed robust upregulation of H19 and its derived miR-675-3p/-5p in resistant cells, with similar induction of H19 in sensitive cells after extended azacitidine exposure. However, functional assays demonstrated that neither H19 overexpression in sensitive K562 and KG1a cells nor its downregulation in resistant cells altered proliferation, apoptosis, or drug response. These results suggest that H19 upregulation reflects epigenetic reprogramming during prolonged drug exposure but does not functionally drive resistance. Our findings refine the role of H19 in AML, highlighting the need to distinguish biomarkers of drug exposure from true mediators of resistance when identifying therapeutic targets in azacitidine-resistant AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312727 | GEO | 2026/01/31

REPOSITORIES: GEO

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Project description:Although 80% of AML patients can initially achieve a complete remission, the long-term disease-free survival is only 40% at 6 years with a 10% 5-year survival rate from first relapse. Most patients do not achieve a second remission. Therefore, relapse after initial response to chemotherapy remains a serious clinical challenge requiring new therapeutic strategies. Annual relapse rates have been calculated 40%, 17%, and 2% in years 1-3, respectively. One of the issues hindering the successful treatment of AML patients, and contributing to disease relapse, is leukaemic cell adhesion and retention in the protective niche of the BMME. Here, the leukaemic cells are surrounded by other cell types that promote their survival, by enabling them to evade destruction by both the immune system and intra-vascular therapies, ultimately leading to the emergence of drug resistance. Given the dependence of AML cells on the BMME, a better understanding of the biological interactions between the leukaemic cells and the haematopoietic niche is needed. In addition, the identification and development of therapies to target these adhesive interactions will enable AML cells to be forced out of their BMME protective niche, into the peripheral circulation, where they will be more susceptible to conventional drug regimens. We have developed and optimised a robust, reproducible, in vitro co-culture model of the AML-BMME. Using the optimised model, several adhesion blocking agents were tested to reduce the number of adhered AML cells. Anti-CD44 treatment was established as the most effective in preventing AML adhesion of OCI-AML3, KG1a and primary AML cells. However, even with maximum dose of the most promising blocking agent, some AML cells still adhered. Following this observation, KG1a and OCI-AML3 cells were treated in co-culture and monoculture. Subsequently paired adhered, non-adhered and monoculture cells were isolated and sent for RNA sequencing in order to perform comparative transcriptomic analysis. The results from these experiments helped us identify novel targets from the persistently adhered AML cells in order to more effectively block their adhesion on our model.

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Long non-coding RNA H19 is overexpressed in azacitidine-resistant K562 cells but does not modulate drug sensitivity [smallRNA-Seq]

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