Tyrosine kinases as therapeutic targets in BCR-ABL negative chronic myeloproliferative disorders.
Acquired constitutive activation of protein tyrosine kinases is a central feature in the pathogenesis of chronic myeloproliferative disorders (CMPDs). The most commonly involved genes are the receptor tyrosine kinases PDGFRA, PDGFRB, FGFR1 or c-KIT and the non-receptor tyrosine kinases JAK2 and ABL. Activation occurs as a consequence of specific point mutations or fusion genes generated by chromosomal translocations, insertions or deletions. Mutant kinases are constitutively active in the absence of the natural ligands resulting in deregulation of haemopoiesis in a manner analogous to BCR-ABL in chronic myeloid leukaemia. With the advent of targeted signal transduction therapy with tyrosine kinase inhibitors, an accurate diagnosis of CMPDs by morphology, karyotyping and molecular genetics has become increasingly important. Imatinib induces high response rates in patients associated with constitutive activation of ABL, PDGFRalpha, PDGFRbeta and some KIT mutants. Other inhibitors under development are promising candidates for effective treatment of patients with constitutive activation of JAK2, FGFR1 and imatinib-resistant KIT mutants.
Reiter
Andreas
A
III. Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany. andreas.reiter@med3.ma.uni-heidelberg.de
Walz
Christoph
C
Cross
Nicholas C P
NC
D002908:Chronic Disease; D004789:Enzyme Activation; D016313:Genes, abl; D006801:Humans; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases