Figure 6.

Potential therapeutic targeting of functionally cooperating molecular mechanisms. Personalized efficient AML therapies will most likely be based on a combination of strategies that target the driver mutation (A), cooperating processes (B), and general characteristics of the transformed state (C). Targeting the driver can be achieved by degradation of the fusion oncogene (e.g., as shown for PML–RARA by ATRA and arsenic) and blocking critical protein–protein interactions (e.g., MENIN–KMT2A interaction for chromosome binding of KMT2A fusions), related enzymatic activities, or essential downstream targets. Cooperating mutations, including constitutive active protein tyrosine kinases or RAS proteins, can be targeted with highly selective and potent small-molecule inhibitors (e.g., FLT3 inhibitors). The transformed state can be impaired by blocking survival by primed BH3-apoptosis regulators (e.g., BCL2, MCL1) or by targeting altered metabolism-related regulators (e.g., mutated IDH1/2).