Targeted signal transduction therapies in myeloid malignancies.
The myeloid malignancies include the myeloproliferative neoplasms (MPN) including chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). A growing body of evidence documents that these diseases are caused by genetic mutations that constitutively activate tyrosine kinases. They include the BCR/ABL in CML, the V617F JAK2 in Philadelphia chromosome-negative MPN, and the Flt3 ITD and TKD mutations in AML. Trials of the ABL kinase inhibitor, imatinib, have revolutionized the treatment of CML, and there are ongoing studies with other kinase inhibitors in MPN and AML. Here we review results of recent studies with first-generation JAK2 inhibitors in the treatment of MPN and second-generation ABL and Flt3 inhibitors in CML and AML, respectively. It is becoming apparent that although these kinase mutations have similar effects in vitro, each of the diseases has unique features that alter the use of kinase inhibitors in the clinic.
Scott
Emma
E
University of Pennsylvania, Philadelphia, 19104, USA.
Hexner
Elizabeth
E
Perl
Alexander
A
Carroll
Martin
M
D002986:Clinical Trials as Topic; D017326:Clinical Trials, Phase III as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis; D016032:Randomized Controlled Trials as Topic; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics
D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D053614:Janus Kinase 2
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