Molecular characterisation of receptor tyrosine kinases in chronic myeloproliferative disorders

Baxter, E. Joanna (2004) Molecular characterisation of receptor tyrosine kinases in chronic myeloproliferative disorders. University of Southampton, Doctoral Thesis.

Abstract

The BCR-ABL negative myeloproliferative disorders (MPDs) are poorly understood at both the clinical and molecular level.  Translocations involving chromosome bands 5q33 and 8p11, which cause rearrangements of the PDGFRB and FGFR1 genes respectively, are found in a minority of these patients.  In this study, the disease that is characteristic of leukaemia with a rearrangement of 5q31-q33 is defined by a literature review of patient reports.  The most common translocation in this group is the t(5;12)(q33;p13) which fuses ETV6 to PDGFRB.  We have found this disease has both myeloproliferative and myelodysplastic features, commonly eosinophilia, monocytosis and splenomegaly.  The probability of transformation to acute myeloid leukaemia (AML) is approximately 20%, therefore this myelodysplastic syndrome/myeloproliferative disorder (MDS/MPD) is less aggressive than BCR-ABL positive chronic myeloid leukaemia (CML).  Using a two colour FISH assay with probes flanking the PDGFRB gene, 5 patients with a translocation involving 5q31-q33 and the MDS/MPD phenotype were identified as having a rearrangement in this gene.  This is an important abnormality to identify, as PDGFRB fusions are sensitive to the tyrosine kinase inhibitor imatinib.

Four patients with a disease very similar to CML were identified as BCR-ABL negative but had a BCR rearrangement.  The t(8;22)(p11;q11) and t(4;22)(q12;q11) translocations were cloned from these cases, and found to result in novel in-frame fusions of BCR to FGFR1 and BCR to PDGFRA respectively.  During this study a novel fusion FIP1L1-PDGFRA was described by Cools et al., (2003) in patients with HES.  Screening of hypereosinophilic syndrome (HES) and atypical CML patients demonstrated that the FIP1L1-PDGFRA fusion was present in 3/34 patients.  Furthermore, screening a cohort of 40 MPD patients, 8 hypereosinophilic syndrome and 10 systemic mastocytosis patients by dHPLC demonstrated that point mutations in KIT, PDGFRA or PDGFRB are uncommon in the MDS/MPD group of disorders.  Defining the molecular basis of these diseases is imperative for treatment of patients with the new generation of specific tyrosine kinase inhibitors.

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