Abstract: Acute myeloid leukemia (AML) is a kind of malignant hematopoietic system disease characterized by abnormal proliferation, poor cell differentiation, and infiltration of bone marrow, peripheral blood, or other tissues. To date, the first-line treatment of AML is still based on daunorubicin and cytosine arabinoside or idarubicin and cytosine arabinoside regimen. However, the complete remission rate of AML is still not optimistic, especially in elderly patients, and the recurrence rate after complete remission is still high. The resistance of leukemia cells to chemotherapy drugs becomes the main obstacle in the treatment of AML. At present, the research on the mechanisms of drug resistance in AML is very active. This article will elaborate on the main mechanisms of drug resistance currently being studied, including drug resistance-related proteins and enzymes, gene alterations, micro RNAs, and signal pathways.


Keywords: drug resistance, P-glycoprotein, gene alterations, signaling pathway


INTRODUCTION

Acute myeloid leukemia (AML) is a kind of malignant clonal disease originating from myeloid progenitors or lymphoid-primed multipotential progenitors.1 With the advancement of chemotherapy, hematopoietic stem cell transplantation, immunotherapy, and molecular targeted therapy, most AML patients can achieve complete remission (CR). The standard regimen, daunorubicin (DA) or idarubicin (IDA) combined with cytosine arabinoside, is still the first-line treatment for AML. The CR rate of first-line treatment is 60%–80% in young adults and 40%–60% in older adults >65 years old.2,3 But nearly 60% of elderly patients failed in inducing chemotherapy due to recurrence, and >85% of patients failed in treatment.4,5 Recently, studies found that drug resistance was the key to treatment failure, which contributed to the short-term survival in AML. Tumor drug resistance is mainly divided into primary drug resistance and acquired drug resistance. Primary drug resistance is the phenomenon that tumor cells, such as cells in the nonproliferative G0 phase, are not sensitive to drugs before the use of antitumor drugs. Acquired resistance refers to the phenomenon that initial tumor cells are sensitive to chemotherapy drugs, but the curative effect of drugs reduces gradually and results in drug resistance after induction therapy.

Residuary drug-resistant cells clone can evolve to predominant clone and make it difficult to be cured.6,7 Although patients can achieve second CR, the relapse-free survival will be worse for patients who did not relapse.8,9 The mechanisms of drug resistance in cancer are still not clear. Many studies have shown that this may be the result of multiple factors. This article reviews the following four common publicly recognized mechanisms of drug resistance in AML and discusses some of the newly discovered specific mechanisms: 1) drug resistance-related protein and enzyme, 2) genetic alterations, 3) miRNAs alterations in drug resistance, and 4) aberrant activation of drug resistance-related signal pathway (Figure 1).

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