Roles of SNHG15 in chemoresistance in acute myeloid leukemia

Details

Supervisors

Havelange, Violaine

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

enAcute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by the clonal proliferation and accumulation of immature myeloid precursor cells (blasts) in the bone marrow and peripheral blood. Prognosis remains poor, with an overall 5-year survival of about 30%, ranging from approximately 50% in younger patients to less than 10% in older individuals. Anthracyclines are the cornerstone of standard “7+3” induction chemotherapy, but remission rates remain limited and relapse is frequent, largely due to chemoresistance. Multiple mechanisms contribute to chemoresistance, including the overexpression of drug efflux transporters, genetic alterations and dysregulated signalling pathways. More recently, long non-coding RNAs (lncRNAs) have emerged as key regulators of leukemic cell behaviour and therapeutic response in AML, prompting the identification of specific lncRNAs potentially involved in anthracycline resistance. Transcriptional profiling previously performed in the laboratory of Prof. Havelange compared doxorubicin-sensitive and -resistant AML cell lines. Among the dysregulated transcripts, SNHG15 emerged as a candidate of interest due to its distinct expression pattern: its expression declined in sensitive cells upon doxorubicin exposure, whereas resistant cells maintained stable levels. Transient knockdown of SNHG15 reduced proliferation of resistant cells upon treatment, suggesting a potential role in chemoresistance. This master’s thesis therefore investigates the role of SNHG15 in mediating resistance to anthracyclines in AML cell models. Prior to functional analyses, sensitivity and resistance profiles of the selected AML cell lines were validated. Cross-resistance between doxorubicin and daunorubicin was observed in doxorubicin-resistant K562 cells, extending the scope of this study to this clinically relevant anthracycline. Differential regulation of SNHG15 upon anthracycline exposure was confirmed. To assess its functional relevance, SNHG15 was stably repressed in resistant K562 cells or overexpressed in sensitive K562 cells. Despite efficient modulation, neither approach significantly altered cell viability or sensitivity to doxorubicin or daunorubicin. SNHG15 knockdown slightly reduced cell viability under basal conditions, while SNHG15 overexpression modestly increased cell viability, suggesting a potential role in leukemogenesis rather than in chemoresistance. Subcellular fractionation revealed that SNHG15 is predominantly nuclear in both doxorubicin-sensitive and -resistant cells. Collectively, these results indicate that while SNHG15 is differentially regulated in response to anthracycline exposure in AML cell lines, its modulation alone is insufficient to drive or reverse chemoresistance in the studied models. These findings suggest that SNHG15 may contribute to stress-responsive regulatory networks or leukemic cell proliferation rather than acting as a primary mediator of anthracycline resistance.