Acute Myeloid Leukemia Signaling

Acute myeloid leukemia (AML), also known as acute myelogenous leukemia, is a cancer of the myeloid line of white blood cells characterized by the rapid proliferation of abnormal cells. Many AML cells have more than one recurring mutation which could include point mutations, gene rearrangements and/or chromosomal translocations. Most genetic alterations in AML cells have been described in myeloid transcription factors that govern hematopoietic differentiation and signal transduction intermediates.Activating mutations of signal transduction intermediates like N-Ras, K-Ras, Kit and Flt3 are found in about 50% of primary AML bone marrow samples. These could result in aberrant and constitutive signal transduction via MAPK and PI3K pathways, leading to increased proliferation and apoptosis resistance.Specific hematopoietic transcription factors are crucial for differentiation to particular lineages during normal differentiation, but are frequently disrupted by loss-of-function genetic alterations in AML. Chromosomal translocations can result in fusion proteins of hematopoietic transcription factors (e.g. AML1-ETO) which inhibit the transactivation by normal transcription factors. In other cases, the transcription factors themselves (e.g. PU.1, C/EBP alpha, AML1) are mutated. Aberrant transcription by these factors results in a loss of myeloid differentiation and proliferation.