Molecular Features and Treatment Paradigms of Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a common hematologic malignancy that is considered to be a disease of aging, and traditionally has been treated with induction chemotherapy, followed by consolidation chemotherapy and/or allogenic hematopoietic stem cell transplantation. More recently, with the use of next-generation sequencing and access to molecular information, targeted molecular approaches to the treatment of AML have been adopted. Molecular targeting is gaining prominence, as AML mostly afflicts the elderly population, who often cannot tolerate traditional chemotherapy. Understanding molecular changes at the gene level is also important for accurate disease classification, risk stratification, and prognosis, allowing for more personalized medicine. Some mutations are well studied and have an established gene-specific therapy, including FLT3 and IDH1/2, while others are being investigated in clinical trials. However, data on most known mutations in AML are still minimal and therapeutic studies are in pre-clinical stages, highlighting the importance of further research and elucidation of the pathophysiology involving these genes. In this review, we aim to highlight the key molecular alterations and chromosomal changes that characterize AML, with a focus on pathophysiology, presently available treatment approaches, and future therapeutic options.

Keywords: acute myeloid leukemia; molecular; targeted therapy.

Figure 1

This figure demonstrates the effects of key mutations and the effect on cellular function. In the cytoplasm, isocitrate is converted to alpha-ketoglutarate (A-KG), but IDH1 mutations lead to the reduction of A-KG to D-2-hydroxyglutarate (D-2-HG) which is an oncometabolite that travels to the nucleus and inhibits TET2, which blocks DNA demethylation; additionally, D-2-HG is created via reduction in the mitochondria by IDH2 mutant enzymes from Krebs cycle-generated A-KG [77,78,79,80,81]. IDH1 inhibitors target the cytoplasmic reduction of A-KG to D-2-HG, while IDH2 inhibitors target the same but in the mitochondria [79,80,81]. NPM1, which normally resides in the nucleolus and minimally binds XPO1, can travel to the nucleoplasm in conditions of stress, where it inhibits HDM2; the inhibition of HDM2 is significant because the normal function of HDM2 is to inhibit TP53 [48,74]. Thus, by inhibiting HDM2, NPM1 can increase TP53 which has important implications for cell regulation in stressful conditions [48,74]. Mutant NPM1 (NPM1c) has a higher affinity to XPO1 and thus is prone to nuclear export, which leads to the export of important nuclear proteins [48,74]. Additionally, the consequent result of mutant NPM1, and XPO1-NPM1c, can lead to increased HOX expression [48,74]. Additionally, NPM1c and KMT2Ar interact with menin, which facilitates leukemogenic cellular changes; this can be targeted via menin inhibition [75]. This figure was adapted from the figures and text in the sources that are cited in this section.