Drug resistance-related microRNAs in hematological malignancies: Translating basic evidence into therapeutic strategies

Abstract

Systemic chemotherapy has been used as the first-line therapy for patients with hematological malignancies. Despite the enormous progress in anti-tumor efficacy achieved during the last decades, the development of multidrug resistance (MDR) remains a major challenge in the successful treatment of hematological malignancies. Extensive investigations have discovered diverse mechanisms underlying MDR. More recently, increasing evidence demonstrates that miRNAs play a key regulatory role in MDR in hematological malignancies through modulating drug transporter-related proteins, cell cycle-related proteins, drug targets, autophagy, tumor microenvironment, cell survival signaling and apoptosis pathways. Pre-clinical evidence suggests that miRNAs may prove to be an ideal biomarker for predicting drug response or clinical outcomes, thus holding much promise for the development of targeted therapies and personalized medicines for the treatment of hematological malignancies. This review focuses on molecular mechanisms underlying miRNA-mediated chemoresistance in hematological malignancies and discusses evidence of transitional research aiming to bring drug resistance-associated miRNAs into clinical settings.

Introduction

Hematological malignancies are primary cancers of the blood and hematopoietic organs such as bone marrow and lymphoid tissues, mainly including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma and multiple myeloma [1].

Current treatment regimens for hematological malignancies mainly consist of chemotherapy, radiotherapy, immunotherapy and hematopoietic stem cell transplantation [2], [3], [4]. Unlike solid tumors, surgery is rarely indicated as a primary treatment modality for hematological malignancies while systemic chemotherapy remains the preferred treatment option and has been used as the first-line therapy. Although the use of chemotherapeutic agents has substantially improved the anti-tumor efficacy, the development of multidrug resistance (MDR) remains a major challenge in the successful treatment of hematological malignancies. Extensive investigations have discovered some mechanisms underlying MDR such as membrane-based export pump P-glycoprotein (P-gp), cell apoptosis related proteins, glutathione S-transferases, drug targets, bone marrow microenvironment and clinical risk factors such as white blood cell count and age [5], [6], [7]. However, the exact mechanisms of MDR in hematological malignancies remain largely unknown. Increasing numbers of recent studies have demonstrated that microRNAs (miRNAs) play a key role in reversing MDR and enhancing the response of blood tumor cells to chemotherapy [8] (Table 1).

miRNAs are short (19–24 nucleotides) noncoding RNA sequences that act mainly by direct base pairing to the 3′-UTR of multiple target messenger RNAs imperfectly or perfectly, resulting in translational repression or mRNA degradation. Lacking the ability to encode proteins, these small non-coding RNAs are important post-transcriptional regulators of gene expression [9], thereby controlling many fundamental physiopathological events such as cell differentiation, proliferation, apoptosis, normal and malignant hematopoiesis [10], [11].

Mutation or aberrant expression of a miRNA-coding gene may cause up- or down-regulation of the miRNAs of interest, thus affecting the function of multiple target mRNAs, altering the expression of multiple proteins that are involved in the drug-resistant signal transduction network, and finally changing the chemosensitivity of tumor cells via complex cellular processes [12], [13] (Fig. 1). miRNAs therefore represent a new set of particularly attractive therapeutic targets in overcoming MDR in hematological malignancies. In addition, differential miRNA expression profiles in serum or plasma samples can be used as non-invasive diagnostic or prognostic biomarkers. Studies on miRNAs have therefore quickly moved from research on the molecular basis of cancer to clinical applications. Specific examples exemplifying the involvement of these miRNAs in MDR are discussed below. Data presented in this review may provide new insights into the exact mechanisms of miRNA-mediated chemoresistance and shed new light on future therapies for hematological malignancies.