Emerging therapies for acute myeloid leukemia: translating biology into the clinic

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a poor outcome; overall survival is approximately 35% at two years and some subgroups have a less than 5% two-year survival. Recently, significant improvements have been made in our understanding of AML biology and genetics. These fundamental discoveries are now being translated into new therapies for this disease. This review will discuss recent advances in AML biology and the emerging treatments that are arising from biological studies. Specifically, we will consider new therapies that target molecular mutations in AML and dysregulated pathways such as apoptosis and mitochondrial metabolism. We will also discuss recent advances in immune and cellular therapy for AML.

Figure 1. FLT3 mutations promote cell proliferation and chemoresistance.

Activating mutations of FLT3 caused by internal tandem duplications (ITDs) or point mutations in the tyrosine kinase domain (TKD) result in constitutive tyrosine kinase signaling. FLT3 signaling recruits pathways, including Ras, PI3-kinase, and STAT5, that promote cellular proliferation and chemoresistance. Illustrated by Rachel Davidowitz.

Figure 2. IDH1/2 mutations lead to increased production of the oncometabolite that alters DNA methylation.

(A) Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) catalyze the conversion of isocitrate to α-ketoglutarate (αKG). αKG, along with Fe(II), is an essential cofactor for TET2 and contributes to the active demethylation of DNA. (B) Mutations in IDH1 and IDH2 alter the affinity of the enzymes for their substrates, leading to conversion of αKG to R-2-hydroxyglutarate (R-2-HG). In addition to αKG depletion, R-2-HG inhibits TET2 and other αKG-dependent enzymes, resulting in DNA hypermethylation. Illustrated by Rachel Davidowitz.