Thus, the present study has elucidated the important differences of signaling mechanisms from the two most important leukemogenic tyrosine kinase mutants, and proposes RSK1 as a promising target, particularly in combination with PIM or PI3K, as well as the anti-apoptotic Bcl-2 family members, for novel therapeutic strategies against therapy-resistant FLT3-ITD-positive AML. Here, PIM1 is linked to acute myeloid leukemia.