Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease with a poor prognosis and remarkable resistance to chemotherapeutic agents. Understanding resistance mechanisms against currently available drugs helps to recognize the therapeutic obstacles. Various mechanisms of resistance to chemotherapy or targeted inhibitors have been described for AML cells, including a role for the bone marrow niche in both the initiation and persistence of the disease, and in drug resistance of the leukemic stem cell (LSC) population. The BM niche supports LSC survival through direct and indirect interactions among the stromal cells, hematopoietic stem/progenitor cells, and leukemic cells. Additionally, the BM niche mediates changes in metabolic and signal pathway activation due to the acquisition of new mutations or selection and expansion of a minor clone. This review briefly discusses the role of the BM microenvironment and metabolic pathways in resistance to therapy, as discovered through AML clinical studies or cell line and animal models.
Highlights
Hematopoietic stem cells (HSCs) produce all blood cell types throughout life due to their capacity for self-renewal and differentiation [1,2]
For hematopoietic stem cell transplantation (HSCT), standard myeloablative conditioning (MAC-HSCT) regimens in acute myeloid leukemia (AML) include Cyclophosphamide and total body irradiation (TBI) or Cyclophosphamide and Busulfan or Fludarabine and Busulfan [39], which is not recommended in patients older than 70 years due to the possibility of toxicity
Some new medications, including Midostaurin (FLT3 inhibitor), Gilteritinib (FLT3 inhibitor), CPX-351, Gemtuzumab-Ozogamicin, Enasidenib (IDH2 inhibitor), Ivosidenib (IDH1 inhibitor), Venetoclax (B-cell lymphoma 2 (BCL-2) inhibitor), and Glasdegib (Smoothened (SMO) inhibitor), have been approved by the Food and Drug Administration (FDA) to be used for AML treatment [46], all of which are targeted therapies aimed at personalizing the approach to management of AML [8]
Summary
Hematopoietic stem cells (HSCs) produce all blood cell types throughout life due to their capacity for self-renewal and differentiation [1,2]. AML relapse is due to various factors, such as dysregulation of the signaling pathways associated with DNA damage response sensing proteins, mutations in cell cycle control genes, changes in programmed cell death (including apoptosis and autophagy), altered anti-cancer drug trafficking, and other mechanisms that still need to be discovered [17,18]. Another important reason why many patients relapse is the inability of most therapies to target the leukemic stem cell (LSC) population [19]. We discuss the various mechanisms contributing to drug resistance in AML, including both intrinsic and extrinsic mechanisms that have been discovered through animal models or clinical investigations
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