Exploring Senescence in Chronic Myeloid Leukaemia Stem Cells as a Source of Treatment Resistance

Abstract

Despite the dramatic improvement of survival in CML patients by Tyrosine kinase inhibitors (TKIs), several resistance mechanisms exist, such as the persistence of treatment-resistant leukaemic stem cells (TR LSCs). TKI was observed to induce cellular senescence in CML cells in vitro, which is defined as the stable cell cycle arrest with accompanying secretory activity. While treatment-induced senescence was studied in therapy resistance and pathogenesis of malignancies like breast and lung cancer, it is yet to be established in CML. Therefore, we hypothesized the presence of senescent cells in CML LSCs. Single-cell RNA sequencing data were utilized to search for transcriptomic senescence hallmarks. Normalized gene expression table and differential gene expression lists of CML LSCs and normal controls were investigated by Gene-set enrichment analysis, gene ontology analysis, and manual database search. There was no enrichment of senescence among CML LSCs. TR LSCs showed positive enrichment of quiescence phenotype compared to normal haematopoietic stem cells, and senescence-associated secretory phenotype (SASP) enrichment with therapy. NFKBIA and WNT pathway genes were upregulated in TR LSCs and LSCs at diagnosis, indicating possible senescence escape and bypass, which are the ability to exit or avoid senescence. In conclusion, the presence of senescent cells in CML stem cells is non-conclusive due to the lack of other senescence markers (e.g., proteomic data), and the absence of a validated CML transcriptomic senescence biomarker. There is a need to experimentally validate senescence biomarkers in CML, which have the potential to study its relationship with leukaemogenesis and response to senolytic therapy.