Investigating Musashi-2 as a Potential Therapeutic Target in Myeloid Leukemia

Abstract

Chronic myeloid leukemia (CML) is a hematologic malignancy characterized by the uncontrolled proliferation of differentiated and functional myeloid cells, including granulocytes (such as neutrophils, eosinophils, and basophils), as well as monocytes. 95% of CML cases are characterized by the presence of BCR-ABL translocation mutation, called Philadelphia chromosome, which is the driver of leukemogenesis. Despite advancements in treatment of CML, which includes tyrosine kinase inhibitors (TKIs) like imatinib, therapeutic challenges remain due to drug tolerance, acquired resistance, and minimal residual disease (MRD), which are largely attributed to leukemic stem cells (LSCs) and senescent cell populations that evade TKI targeted eradication. Musashi-2 (MSI2) is overexpressed in CML, particularly in aggressive cases making it a prognostic marker of poor outcome. The role of MSI2 in CML LSC and senescence is not known therefore we explored MSI2 in in the proliferation and senescence in CML sensitive and resistant models. In this study, we assessed the antiproliferative potential of MSI2 inhibition in CML using pharmacological and biochemical targeting. Our results demonstrated that MSI2 expression was elevated in both sensitive (p value 0.0004) and imatinib-resistant K562 cells (p value <0.0001). MSI2 inhibition significantly reduced cell viability and colony formation in both sensitive (p value < 0.001) as well as resistant (p value < 0.001) cell models, with an additive effect observed in combination with imatinib in sensitive cells (p value 0.002) and a synergistic effect in resistant cells (p value 0.0017). Mechanistic studies indicated induction of slight apoptosis through DNA fragmentation assay Furthermore, exploring cell cycle inhibitors revealed downregulation of p21 (p value 0.0052), p27 (p value 0.0015), and p16 (p value 0.0025), and the upregulation of p53 (p value 0.004). The senescent marker IL-6 was also downregulated in the resistant model. Additionally, MSI2 inhibition led to significant downregulation of key components of the Wnt/β-catenin signaling pathway, c-Myc (p value 0.0128), HIF-1α (p value 0.0050), and Eya3 (p value 0.0008) in both sensitive and resistant models. Based on our findings, we conclude that combining MSI2 inhibition with TKI therapy overcomes drug resistance, addresses cellular senescence, and potentially targets LSCs in CML