Molecular mechanisms of therapeutic intervention in acute myeloid leukemia (AML).
Schematic representation of the FLT3-ITD signaling pathways and downstream effects in acute myeloid leukemia. FLT3-ITD is a constitutively active growth factor receptor signaling via PI3K-AKT, via RAS-MEK-ERK, and via STAT5 leading to cell growth and proliferation via p53 inhibition and MCL1 induction. p53 function can be reactivated by APR-246 treatment leading to inhibition of MCL1 gene expression. MCL1 function can be inhibited by S63845, by PTC596 via BMI1 inhibition, and by APR-246 via p53 induction. Oncogenic functions are indicated in red, tumor suppressor functions in green, chemical inhibitors in pink, chemical activators in blue.
Induction of apoptosis and cell death in acute myeloid leukemia (AML) treated with targeted compounds.
Imaging cytometry of annexin V stained AML cells (MOLM-13) treated for 20 hrs with targeted compounds alone
A) mock-treated, B) MCL1 inhibitor S63845, C) MDM2 inhibitor HDM201, D) FLT3 inhibitor PKC412, E) MEK inhibitor trametinib, F) BMI1 inhibitor PTC596, and in combination G) PTC596 and S62834, H) PTC596 and HDM201, J) PTC596 and PKC412, K) PTC596 and trametinib, depicting induction of apoptosis and cell death using annexinV and PI staining.
Seipel K, Kopp B, Bacher U, Pabst T. Cancers (Basel). 2021 Feb 2;13(3):581. doi: 10.3390/cancers13030581.
