Deciphering the Therapeutic Resistance in Acute Myeloid Leukemia

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.

Gene Transcription as a Therapeutic Target in Leukemia

“…Nevertheless, there are certain cohorts with poor prognosis; patients > 60 years with AML demonstrate only 40–60% of remission with overall 24% 5 year survival [ 239 ], while ALL is the leading cause of cancer related deaths among children [ 240 ]. Therapy failure is often associated with drug resistance; in addition to 35–45% of resistant tumors among newly diagnosed cases, relapsed tumors almost never respond to the previously used therapy [ 241 ]. Sometimes the genetic basis of this resistance cannot be found (reviewed in [ 4 ]); hematological malignancies (with the high rate of pediatric cases), especially AML, carry relatively low mutation burden.…”

“…Sometimes the genetic basis of this resistance cannot be found (reviewed in [ 4 ]); hematological malignancies (with the high rate of pediatric cases), especially AML, carry relatively low mutation burden. In AML, about 40% of resistant tumors show no signs of nonsynonymous coding mutations responsible for resistance [ 241 ].…”

Immunoproteasome Activity in Chronic Lymphocytic Leukemia as a Target of the Immunoproteasome-Selective Inhibitors

“…The treatment of these hematological malignancies has considerably improved in the past years with the recent approval of several novel agents for the treatment of AML, B-ALL, B-CLL and MM, which contributed to expanding the palette of therapeutic options in these diseases [ 1 , 2 , 3 , 4 ]. However, the main reason for treatment failure in a significant proportion of adult patients with leukemias or MM is the occurrence of intrinsic or acquired drug resistance in a subset of malignant cells that is responsible for the development of relapse or refractory disease with a dismal prognosis [ 5 , 6 , 7 , 8 ]. Subsequently, as the development of drug resistance is one of the limiting factors affecting long-term efficacy of anti-leukemic or anti-myeloma drugs, the search for therapies with novel mechanisms of action is an ongoing challenge.…”

CSF1R Inhibition Combined with GM-CSF Reprograms Macrophages and Disrupts Protumoral Interplays with AML Cells

“…However, they remain restricted to a small number of AML categories. Over time and regardless of the treatment, the tumor microenvironment strongly contributes to promoting the growth and survival of drug-resistant subclones, leading to relapse [ 4 , 5 ]. Several clinical studies have demonstrated that heavy tumor infiltration by MΦs is of poor prognosis: tumor-associated macrophages (TAMs) promote tumor cell growth, resistance to treatment, and escape from immune surveillance [ 4 , 6 ].…”