Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1

Area of Science:

• Hematology
• Molecular Biology
• Cancer Research

Background:

• Acute myeloid leukemia (AML) often involves mutations like FLT3 internal tandem duplications (ITD).
• FLT3 inhibitors (FLT3i) treat FLT3-ITD+ AML but resistance frequently develops.
• Understanding resistance mechanisms is crucial for improving AML treatment outcomes.

Purpose of the Study:

• To investigate the gene regulatory network (GRN) alterations driving FLT3 inhibitor resistance in AML.
• To identify mechanisms by which cytokines like IL-3 confer resistance to FLT3 inhibitors.
• To explore therapeutic strategies to overcome cytokine-mediated resistance.

Main Methods:

• Comparative analysis of GRNs in leukemic cells from AML patients before and after relapse.
• Assessment of cytokine (IL-3) effects on FLT3-inhibited cells.
• Evaluation of AP-1 and RUNX1 chromatin binding under FLT3 inhibition and IL-3 treatment.
• Testing the efficacy of a pan-RAS inhibitor in overcoming cytokine-mediated resistance.

Main Results:

• Relapsed AML exhibits altered GRNs, specifically rewiring of the AP-1-RUNX1 axis.
• FLT3 inhibitors upregulate signaling genes, and cytokines like IL-3 can restore cell cycling.
• IL-3 counteracts FLT3 inhibition by restoring AP-1 and RUNX1 chromatin binding.
• A pan-RAS inhibitor effectively overcomes IL-3-induced drug resistance in AML.

Conclusions:

• Cytokines mediate AML growth through the AP-1 and RUNX1 transcriptional regulators.
• The AP-1-RUNX1 axis and cytokine signaling are key pathways in FLT3 inhibitor resistance.
• Pan-RAS inhibitors represent a promising strategy to bypass and overcome resistance mechanisms in AML.