Imatinib molecular biology to therapy

Gleevec Clinical Trials

From the above discussion, it should be clear that the BCR-ABL possesses many characteristics of an ideal therapeutic target. It is expressed in the majority of patients with CML and it has been shown to be the cause of CML. BCR-ABL functions as a constitutively activated tyrosine kinase and mutagenic analysis has shown that this activity is essential for the transforming function of the protein. Thus, an inhibitor of the BCR-ABL kinase would be predicted to be an effective and selective...

Molecular regulation of hematopoiesis

The molecular nature of stem cell regulatory pathways has been determined using a variety of genetic approaches, including genetic loss-of-function and gain-of-function studies. These have provided several important concepts regarding the molecular control of hematopoiesis. First, some genes have binary functions and are either on or off in various biological states, while other genes function in a continuum and have different effects at different levels. Secondly, while perturbations in single...

Intestinal iron transport

Ferroxidase Ferrireductase

Our current understanding of intestinal non-heme iron transport is illustrated in Figure 13.1. Iron absorption takes place in an acidic environment in the proximal small intestine, just distal to the gastric outlet. Most non-heme dietary iron is in the ferric (Fe3+) form. It is reduced to Fe2+ by a brush border ferrireductase, most likely the recently identified duo- Fig. 13.1 Current understanding of intestinal non-heme iron absorption The cartoon shows an absorptive enterocyte from the...

Immunopathogenesis of idiopathic aplastic anemia

The most direct evidence that IAA may be an autoimmune disorder has come from the clinical observation that patients Table 12.4 Classification of the bone marrow failure (BMF) syndromes. Table 12.4 Classification of the bone marrow failure (BMF) syndromes. Autosomal dominant Autosomal recessive Neutropenia, exocrine pancreatic insufficiency, metaphyseal dysostosis Absent megakaryocytes in bone marrow, late BMF Thrombocytopenia with absent radii syndrome Bilateral radial aplasia, lower limb...

Multistep pathogenesis of AML

These data suggest that at least two mutations are required for the development of AML. Genotypic analysis of known leukemia oncogenes indicates that there are at least two broad complementation groups of mutations. One class of mutations, exemplified by FLT3-ITD or oncogenic RAS mutations, confer a proliferative and or survival advantage on hematopoietic progenitors, but have minimal effects on differentiation programs in hematopoietic progenitors. These mutations are each relatively frequent...