1. ¹Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA
2. ²Wessex Regional Genetics Laboratory, Salisbury and Human Genetics Division, University of Southampton, Southampton, UK
3. ³III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany

Correspondence: Professor A Reiter, III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Theodor-Kützer-Ufer 1-3, 68617 Mannheim, Germany. E-mail: andreas.reiter@med3.ma.uni-heidelberg.de

Received 19 February 2008; Revised 24 April 2008; Accepted 25 April 2008; Published online 5 June 2008.

Abstract

Constitutively activated mutants of the non-receptor tyrosine kinases (TK) ABL1 (Abelson murine leukemia viral (v-abl) homolog (1) protein) and JAK2 (JAnus Kinase 2 or Just Another Kinase 2) play a central role in the pathogenesis of clinically and morphologically distinct chronic myeloproliferative disorders but are also found in some cases of de novo acute leukemia and lymphoma. Ligand-independent activation occurs as a consequence of point mutations or insertions/deletions within functionally relevant regulatory domains (JAK2) or the creation of TK fusion proteins by balanced reciprocal translocations, insertions or episomal amplification (ABL1 and JAK2). Specific abnormalities are correlated with clinical phenotype, although some are broad and encompass several World Health Organization-defined entities. TKs are excellent drug targets as exemplified by the activity of imatinib in BCR-ABL1-positive disease, particularly chronic myeloid leukemia. Resistance to imatinib is seen in a minority of cases and is often associated with the appearance of secondary point mutations within the TK domain of BCR-ABL1. These mutations are highly variable in their sensitivity to increased doses of imatinib or alternative TK inhibitors such as nilotinib or dasatinib. Selective and non-selective inhibitors of JAK2 are currently being developed, and encouraging data from pre-clinical experiments and initial phase-I studies regarding efficacy and potential toxicity of these compounds have already been reported.