Acute myeloid leukemia (AML): Based on its fundamental role in induction of cell cycle arrest and apoptosis there is a tight regulation of the function of the tumor suppressor p53 in normal cells. In tumor cells, however, p53 function is frequently inactivated enabling evasion of growth control and outgrowth of malignant cells. In acute myeloid leukemia (AML), p53 function is rarely disrupted by TP53 gene mutations, but more often by dysregulation of p53 interacting proteins including nucleophosmin (NPM1), the cellular p53 inhibitor MDM2, and the nuclear export protein XPO1/CRM1. AML blast cells often carry mutations in the NPM1 gene, and levels of MDM2 and XPO1 are elevated. In addition to p53 inactivation, there may be activation of oncogenes in the leukemic cell. A key oncogene in AML is the FMS-kinase 3 (FLT3) gene. This growth factor receptor is overexpressed in the majority of AML cells or constitutively active in AML cells with FLT3 mutation, observed in up to 30% of AML patients. FLT3 receptor signaling promotes cell survival and prevents apoptosis via activation of the PI3K-AKT kinase cascade and via RAS GTPases to the MAP kinase cascade. FLT3-ITD is a constitutively active FLT3 receptor signaling via PI3K-PDK1-AKT, via RAS-RAF-MEK-ERK and via STAT5.
CAR T-cell therapy: Chimeric antigen receptors target the antigen CD19, present in B-cell-derived cancers such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL), or the BCMA antigen, present in multiple myeloma. There are also emerging CAR T-cell therapies targeting other blood cancer antigens, including CD33, CD123 and FLT3 in acute myeloid leukemia (AML).
GATA2 deficiencies: Mutations in the key transcription factor GATA2 can cause myelodysplastic syndromes and acute myeloid leukemia.