Abstract
The development of Imatinib mesylate (IM), which targets the oncogenic BCR-ABL fusion protein, has greatly improved the outcome of Chronic Myeloid Leukemia (CML) patients. However, BCR-ABL–positive progenitors can be detected in CML patients in complete cytogenetic response. Several evidence suggests that CML stem cells are intrinsically resistant to Tyrosine Kinase Inhibitors (TKI), and therefore they represent the most likely candidate responsible for disease relapse.In this work, we investigated the microRNA (miRNA) expression profile of different subpopulations of CML Leukemic Stem Cells (LSCs): Lin-CD34+CD38- and Lin-CD34-CD38- cells. These cell fractions have been previously shown to be endowed with TKI intrinsic resistance. Our analysis identified 33 common deregulated miRNAs in CML LSCs. Among those, 8 miRNAs were deregulated in CML independently from BCR-ABL kinase activity and therefore are likely to be involved in the BCR-ABL-independent resistance to TKI that characterizes CML LSCs. In particular, the up-regulation of miR-29a-3p and miR-660-5p observed in CML LSCs, led to the down-regulation of their respective targets TET2 and EPAS1 and conferred TKI-resistance to CML LSCs in vitro. On the other hand, miR-494-3p down-regulation in CML LSCs, leading to c-MYC up-regulation, was able to decrease TKI-induced apoptosis. These results demonstrate that aberrant miRNA expression in CML LSCs could contribute to the intrinsic TKI-resistance observed in these cell populations, and support the development of novel therapies aimed at targeting aberrantly regulated miRNAs or their targets in order to effectively eradicate CML LSCs.
Highlights
Chronic Myeloid Leukemia (CML) is a stem cellderived malignant disorder characterized by the reciprocal translocation t(9;22) leading to the BCR-ABL fusion gene
MiR-494-3p down-regulation in CML Leukemic Stem Cells (LSCs), leading to c-MYC up-regulation, was able to decrease Tyrosine Kinase Inhibitors (TKI)-induced apoptosis. These results demonstrate that aberrant miRNA expression in CML LSCs could contribute to the intrinsic TKIresistance observed in these cell populations, and support the development of novel therapies aimed at targeting aberrantly regulated miRNAs or their targets in order to effectively eradicate CML LSCs
Principal Component Analysis (PCA) revealed that CML Lin-CD34-CD38are closer to leukemic CD34+CD38+ and normal CD34+ subfractions whereas their normal counterparts cluster separately, in agreement with our previous findings on the gene expression profile [6]
Summary
Chronic Myeloid Leukemia (CML) is a stem cellderived malignant disorder characterized by the reciprocal translocation t(9;22) leading to the BCR-ABL fusion gene. The BCR-ABL Tyrosine Kinase Inhibitors (TKIs), such as Imatinib mesylate, are the standard therapy for CML patients. Imatinib has been shown to induce complete molecular response in more than 80% of newly diagnosed patients in chronic phase [2]. It has been unable to completely eliminate BCR-ABL-expressing leukemic cells [3]. Corbin et al demonstrated that CML LSCs survive IM treatment independently of BCR-ABL kinase activity [4]. It is clear that a definitive treatment for CML requires the elimination of LSCs. gaining further understanding on the molecular and functional properties of the stem cell compartment in CML is mandatory for the development of more effective therapies that will eliminate TKI-resistant LSCs
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