Tyrosine kinase fusion genes in chronic myeloproliferative diseases

Abstract

With the exception of chronic myeloid leukemia (CML), chronic myeloproliferative disorders (CMPDs) are a heterogeneous spectrum of conditions for which the molecular pathogenesis is not well understood. Most cases have a normal or aneuploid karyotype, but a minority present with a reciprocal translocation that disrupts specific tyrosine kinase genes, most commonly PDGFRB or FGFR1. These translocations result in the production of constitutively active tyrosine kinase fusion proteins that deregulate hemopoiesis in a manner analogous to BCR-ABL. With the advent of targeted signal transduction therapy, an accurate clinical and molecular diagnosis of CMPDs has become increasingly important. Currently, patients with PDGFRB or ABL fusion genes are candidates for treatment with Imatinib (STI571), but it is likely that alternative strategies will be necessary for the treatment of most other patients.

Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia, high‐risk myelodysplastic syndrome, and myeloproliferative disorders

“…[15][16][17]31 In this regard, the activity observed in patients with MF is noteworthy. Most patients had a significant decrease in spleen size.…”

“…Tyrosine kinase fusion genes have been identified in CMML and atypical CML patients. 17 These typically fuse PDGF-RB with one of at least four different genes described to date. 36 -39 These patients usually have chromosomal translocations involving chromosome 5q33.…”

“…In addition, some patients with chronic myelomonocytic leukemia (CMML) present with reciprocal translocations involving the PDGF-RB gene. 17 Most patients with AML and high-risk MDS die of their disease. There is no effective standard therapy for MPD that can change significantly the course of the disease.…”

Fusion tyrosine kinases: a result and cause of genomic instability

“…These unique chromosomal rearrangements have been coupled with specific cancers and have become a vital tool for clinical diagnoses (Cross and Reiter, 2002). Hungerford and Nowell discovered the first of these genetic hallmarks in 1960 at the University of Pennsylvania (Nowell and Hungerford, 1960).…”

“…The first role is stimulation of signaling pathways, which contribute to malignant transformation, including proliferation in the absence of growth factors, protection from apoptosis in the absence of external survival factors and invasion (Kolibaba and Druker, 1997;Liu et al, 2000;Cross and Reiter, 2002;Arlinghaus and Sun, 2004). The second role of FTKs in hematological malignancies is the modulation of responses to DNA damage, rendering cells resistant to genotoxic therapies and causing genetic instability (Alimena et al, 1987;Kelman et al, 1989;Laneuville et al, 1992;Bedi et al, 1995;Nishii et al, 1996;Amarante-Mendes et al, 1998;Dubrez et al, 1998;Villamor et al, 1999;Honda et al, 2000;Salloukh and Laneuville, 2000;Sercan et al, 2000;Aoki et al, 2001;Greenland et al, 2001;Slupianek et al, 2001).…”