Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106
USA

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Molecular Pathogenesis of Philadelphia-Positive Chronic Myeloid Leukemia – is it all BCR-ABL?

Author(s): H. Rumpold, G. Webersinke.

Abstract:

CML is characterized by the presence of the Philadelphia chromosome, which is the product of a reciprocal translocation between chromosomes 9 and 22 that results in the formation of BCR-ABL1. Apart from its diagnostic importance in CML patients BCR-ABL1 it is a potent oncogene. The natural evolution of CML is to progress into accelerated phase and blast crisis after a rather indolent chronic phase. Clinical experience shows that long term remissions can be achieved at a high rate at least in chronic phase by specific inhibition of BCR-ABL1. This underlines the importance of BCR-ABL1 at this stage of the disease. However, in accelerated phase and blast crisis the effect of these substances is of inferior importance as relapses are the rule rather than the exception. Treatment failure in advanced disease is frequent in patients without detectable resistance mechanisms such as BCR-ABL1-mutations, which suggests that the previously BCR-ABL1 dependent pathways probably become autonomous. Such pathways include signal transduction as well as DNA damage surveillance and repair. Especially the latter appear to be crucial for disease progression by causing genetic instability, accumulation of mutations and additional chromosomal alterations leading to the loss of tumor suppressors. How is BCR-ABL1 organized on the genetic level, is there a genetic precursor lesion as discussed for Philadelphianegative myeloproliferative diseases, what is its role in pathogenesis and progression of CML and what is its role in the CML-stem cell? These questions will be discussed in this review.

Keywords: BCR-ABL, CML, pathogenesis, molecular genetics, chronic myeloproliferative diseases, Chronic Myelogenous Leukemia, Leukemia, Mastocytosis, diagnostic, chromosome, oncogen, stem cells, MOLECULAR BIOLOGY, cytoplasm, tyrosine kinase, plekstrine homology domain, toxin substrate, phosphorylation of tyrosine, immune system, bone marrow cells, haematopoiesis, pulmonary haemorrhages, PH-TRANSLOCATION, risk factor, phenotype, heterozygous, myeloproliferative nepolasms, myeloid colony, phenylalanine, leukemic cell, cell, phosphorylation, antiapoptotic protein, michochondrial cytochrome-c, mRNA, disease progression, Granulocytemacrophage progenitor cells, mutation rate, clonogenicity potential, STEM CELL, haematopoietic stem cells, immunocompromised, immunophenotyping, xenografts, chemotherapeutics, radiation, monoclonal antibody, cytotoxic effect, genetic instability

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Article Details

VOLUME: 11
ISSUE: 1
Year: 2011
Page: [3 - 19]
Pages: 17
DOI: 10.2174/156800911793743619