Proposal for a sixgroup translocation cyclin D classification of multiple myeloma tumors

In addition to determining the expression level of cyclin D1, 2 and 3, gene expression profiling can effectively identify MM tumors that overexpress the oncogenes dysregulated by the five recurrent IgH translocations 11q13 (cyclin D1) 6p21 (cyclin D3) 4p16 (MMSET and usually FGFR3) 16q23 (c-maf) and 20q11 (mafB). We propose six translocation cyclin D (TC) groups (Table 11.1) that can be distinguished on the basis of five recurrent Ig translocations and cyclin D expression. (1) The 11+6 group...

Chronic lymphocytic leukemiassmall cell lymphoma

Chronic lymphocytic leukemia is a low-grade lymphoma marked by a peripheral lymphocytosis of CD5+, CD20+, CD23+ small lymphocytes that are similar in morphology to normal lymphocytes. BCL-2, which is expressed at low levels in normal lymphocytes, is expressed at high levels in more than 70 of CLL cases but this is rarely, if ever, due to a t(14 18). Staging based on presence of lymphadenopa-thy, organomegaly anemia or thrombocytopenia can provide prognostic information, those in the best...

Cytogenetic abnormalities

Clearly, since MDS can progress to AML, all of the cytoge-netic abnormalities found in MDS are also found in AML, although their incidence will differ between MDS and AML. However, certain balanced translocations found in AML are never found in MDS, including the t(15 17), inv(16), t(8 21) Table 8.1 International Prognostic Scoring System. Poor (chromosome 7) or complex (> 3 abnormalities) *Cytopenia is defined as platelet count < 100 x 109 L, hemoglobin < 10 g dl, or neutrophil count <...

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...

Chromosome abnormalities

Asimakopoulos FA, Green AR. (1996) Deletions of chromosome 20q and the pathogenesis of myeloproliferative disorders. British Journal of Haematology, 95, 219-226. Bench AJ, Nacheva EP, Champion KM, Green AR. (1998) Molecular genetics and cytogenetics of myeloproliferative disorders. Bailliere's Clinical Haematology, 11, 819-848. Bench AJ, Cross NC, Huntly BJ et al. (2001) Myeloproliferative disorders. Best Practice & Research. Clinical Haematology, 14, 531-551. Berger R, Bernheim A, LeConiat...

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...

The structure genetic control and synthesis of normal hemoglobin

Mechanism Globin Chain Synthesis

The varying oxygen requirements during embryonic, fetal and adult life are reflected in the synthesis of different structural hemoglobins at each stage of human development. They all have the same general tetrameric structure, however, consisting of two different pairs of globin chains, each attached to one heme molecule. Adult and fetal hemoglobins have a chains combined with P chains Hb A, a2P2 , 8 chains Hb A2, a282 and y chains Hb F, a2y2 . In embryos, a-like chains called Z chains combine...