A microRNA prevents resistance to targeted therapy in chronic myeloid leukemia

© Non-coding RNA Investigation. All rights reserved. Non-coding RNA Investig 2020 | http://dx.doi. org/10.21037/ncri-2020-006 The treatment of chronic phase chronic myeloid leukemia (CML) was revolutionized by the introduction of imatinib mesylate and later generations of tyrosine kinase inhibitors (TKIs) that potently inhibit the chimeric BCR-ABL kinase, whose aberrant activity both defines CML and underlies its molecular pathogenesis (1). These novel compounds helped establish a new paradigm for cancer treatment focused on targeted therapies that specifically inhibit the dysregulated or hyperactive signaling kinases that frequently drive malignant progression, a strategy which has now been successfully applied to many other hematologic malignancies and solid tumors. Nevertheless, many challenges still remain in treating CML patients including selection of best initial therapy based on patientand disease-specific characteristics, managing acquired resistance to therapy, and more effectively targeting the leukemic stem cell population to achieve better disease control and potentially a cure. Currently, initial treatment is generally guided by validated risk scores such as the Sokal score or the Hasford score which predict the aggressiveness of disease, and are determined by the patient’s age and clinical features such as spleen size and various hematologic parameters such as blast count and platelet count (2,3). The first generation TKI, imatinib, is generally reserved for patients with lowrisk disease, while the second generation TKIs, bosutinib, dasatinib, or nilotinib, are often preferred initial therapies for patients with intermediateor high-risk disease, though other factors such as patient age and comorbidities and drug side effect profiles also inform treatment selection (4-7). Response to treatment is assessed by monitoring BCR-ABL transcript levels and, if these transcript levels either do not decline as expected or begin to increase, then evaluating for acquired mutations in BCR-ABL that are associated with resistance to particular TKIs, which would prompt a change in TKI therapy. This mutation profiling is epitomized by the T315I mutation in BCR-ABL which predicts resistance to all TKIs except the third generation TKI, ponatinib (7-9). Notably, molecular features such as gene expression or microRNA profiles have not been included in risk stratification, therapeutic resistance profiling, or treatment selection, though emerging research shows their great potential in both CML and other malignancies. A rapidly expanding literature on the contributions of microRNAs to the development and progression of myeloid malignancies, including CML and acute myeloid leukemia (AML), continues to reveal new microRNA targets and their pathologic mechanisms, such as recent reports demonstrating the crucial function of miR-155 in FLT3-ITD AML (10,11). Multiple molecular events can cause microRNA dysregulation in myeloid mal ignancies , including dysregulated microRNA processing, gene deletion or mutation, or epigenetic alterations, all of which can have potential consequences for disease behavior and prognosis (12). Several studies investigating the roles of microRNAs in Editorial Commentary