The effect of c-KIT and NPM 1 mutations on myeloblast proliferation and differentiation

Abstract

Acute myeloid leukemia (AML) is a heterogeneous group of malignancies arising from myeloid stem cell (1,2). The outcome of AML is ominous most of the time. The prognosis and treatment of AML (and other leukemias as well) is dependent on many genetic mutations and chromosomal aberrations present with the disease. The classification of AML is also based on morphology, cytochemistry and genetic markers. Except for the recurrently defined chromosomal aberrations such as t(9;21), t(15;17), inv(l)6, t(9; 11), the majority (more than 50%) of AML carries normal karyotype with no underlying recurrent genetic abnormality (1,2). Two novel mutations identified in some haematological and non haematological neoplasia include mutations in c-KIT gene and NPM 1 gene. c-KIT is a proto-oncogene which encodes a transmembrane tyrosine kinase . Ill receptor (3,4). With its ligand stem cell factor, c-KIT receptor has been shown to be important for cell growth, function and survival of cells. It belongs to the same family of receptors, in Monocyte Colony Stimulating Factor (M-CSF), PDGF and FLT 3. It is expressed in many different human cells including normal haemopoietic precursor cells, mast cells, germ cells and melanocytes etc. Its activation leads to a cascade of phosphorylations in the cytoplasm. It has been implicated in many none haemopoietic malignancies including cancers in breast, lung, ovaries etc (3,4,5,6,). Almost all primary systemic mastocytosis patients show c-KIT mutations specially one named as c-KIT 816 (D816V). Over-expression of c-KIT receptor in myeloblasts was observed in 60-80% of AML. Point mutations of c-KIT gene were exclusively associated with Core Binding Factor AML (CBF-AML) which constitutes about 33-45% of AML and showed higher relapse rate. This could be related to direct effect of mutated c-KIT gene. The relapse and worse prognosis in AML sub types with inv (16) and t (8;21) were associated with c-KIT mutations even though these subtypes fall in to good prognosis category (5-12).