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Review
. 2020 Nov 12;21(22):8505.
doi: 10.3390/ijms21228505.

Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia

Carmelo Gurnari  1   2 , Simona Pagliuca  1 , Valeria Visconte  1
Affiliations
Review

Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia

Carmelo Gurnari et al. Int J Mol Sci. .

Abstract

Acute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by abnormal proliferation, lack of cellular differentiation, and infiltration of bone marrow, peripheral blood, or other organs. Induction failure and in general resistance to chemotherapeutic agents represent a hindrance for improving survival outcomes in AML. Here, we review the latest insights in AML biology concerning refractoriness to therapies with a specific focus on cytarabine and daunorubicin which still represent milestones agents for inducing therapeutic response and disease eradication. However, failure to achieve complete remission in AML is still high especially in elderly patients (40-60% in patients >65 years old). Several lines of basic and clinical research have been employed to improve the achievement of complete remission. These lines of research include molecular targeted therapy and more recently immunotherapy. In terms of molecular targeted therapies, specific attention is given to DNMT3A and TP53 mutant AML by reviewing the mechanisms underlying epigenetic therapies' (e.g., hypomethylating agents) resistance and providing critical points and hints for possible future therapies overcoming AML refractoriness.

Keywords: acute myeloid leukemia; chemotherapy resistance; hypomethylating agent resistance.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Mechanisms of chemoresistance in AML. Examples of the heterogeneity of mechanisms causing chemoresistance in adult acute myeloid leukemia: (A) Biology of the disease: constitutive activation of FLT3 leading to hyperproliferation and oncogenic activation of p53 through DNA damage induction. (B) Host factors: allele polymorphism leading to resistance to daunorubicin and cytosine arabinoside (Ara-C) and tumor microenvironment. Images were generated using BioRender.
Figure 2
Figure 2
Actionable mechanisms to overcome chemoresistance in AML. (A) Exosomes are extracellular vesicles of 30–100 nm in diameter released from body fluids serving as natural nanocarriers with the possibility to manipulate their structure for clinical use. (B) Nanomedicine comprehends a variety of different nanoscale drug delivery systems possibly useful for better delivery of chemotherapy agents. (C) Human leukocyte antigen (HLA) machinery disruption via genetic (mutations) or epigenetic (downmodulation of the expression) mechanisms may lead to immune system evasion. (D) The study of gene regulation via miRNA or lncRNA may represent a useful tool to identify biomarkers of chemosensitivity being promising as also potential therapeutic targets. Images were generated using BioRender.
See this image and copyright information in PMC

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