Investigating possible bypass mechanisms to sensitize AML blasts for combination therapy:Targeting ligand induced receptor tyrosine kinase signaling

Leukemia is the most common form of pediatric cancer and the acute myeloid variant still confers the poorest outcome. Therefore, we attempted to contribute to the understanding of cellular mechanisms and the proteins involved that contribute to acute myeloid leukemia (AML) growth, differentiation blockade, and cellular resistance in AML and their adaptation opportunities for therapeutic intervention. We investigated how we can identify cellular resistance and develop combination therapies that interfere with AML survival with minimal effects on their normal counterparts so that therapeutic toxicity is limited. Five important major drivers of AML maintenance were appointed in the thesis as important characteristics that need to be tackled for therapeutic intervention: 1) AML proliferation advantage 2) AML differentiation blockade 3) AML metabolism for self-sufficiency, 4) altered AML DNA damage response system, and 5) AML cell receptor availability for therapeutic resistance facilitating pathways