The BCR-ABL fusion
The BCR-ABL fusion oncogene is a hallmark of CML. Using sensitive RT-PCR techniques, a number of reports have suggested that a proportion of patients with ET, PV or IMF express the BCR-ABL fusion transcript. However, this observation has not been universally confirmed and is likely to represent identification of very low levels of the transcript. Detection of such low levels of BCR-ABL transcripts is unlikely to be relevant to the pathogenesis of the MPDs since similar results have been obtained using blood from normal individuals.
The 8p11 syndrome is a rare, atypical MPD with a balanced translocation involving chromosome 8p11. Patients commonly present with lymphadenopathy and general malaise. Bone marrow and peripheral blood show myeloid proliferation, frequently with eosinophilia, and there is a high incidence of T-cell non-Hodgkin's lymphoma. Almost invariably, the disease progresses to AML and has a poor prognosis. Cytogenetic examination has revealed a t(8;13)(p11;q12) translocation or, more rarely, t(8;9)(p11;q34) or t(6;8)(q27;p11) translocations. This syndrome appears to result from transformation of a progenitor with both myeloid and lymphoid potential since cytogenetic analysis of lymph node and bone marrow from the same patient revealed the same chromosomal abnormality.
Molecular characterization of these translocations revealed that they all disrupt the FGFR1 gene on 8p11. FGFR1 encodes fibroblast growth factor receptor 1 and is a member of the receptor tyrosine kinase family. As a consequence, FGFR1 becomes fused with three different partner genes: ZNF198 on chromosome 13q12, CEP110 at 9q34 and FOP at 6q27. Subsequently, a translocation t(8;22)(p11;q11) in patients with a CML-like disease was shown to result in a fusion between BCR and FGFR1 and a rare t(8;19)(p12;q13) translocation fused a retrovirus gene, HERV-K, to FGFR1 in a patient with atypical MPD. In addition, a further three translocations involving FGFR1 have been reported, although partner genes have not been cloned.
Fusion proteins involving tyrosine kinases are a common theme amongst myeloid malignancies (Figure 9.7). The first to be described was the BCR-ABL fusion gene generated by the t(9;22) translocation in CML. The BCR-ABL fusion protein contains the coiled-coil oligomerization motif from BCR fused to the majority of the ABL protein containing a tyrosine kinase domain. The t(5;12) translocation in patients with chronic myelomonocytic leukemia (CMML) results in the fusion of the helix-loop-helix domain of the ETS-like transcription factor, TEL, with the tyrosine kinase domain of the PDGFRP protein. In a similar fashion, ZNF198-FGFR1 contains a proline-rich oligomerization domain from ZNF198 fused to the tyrosine kinase domain of FGFR1. Thus, a common activation mechanism links these fusion products. Ligand-independent dimerization leads to constitutive tyro-sine kinase activation and phosphorylation of downstream targets. These oncogenic products are also potentially linked
Putative oligomerization Tyrosine kinase
Fig. 9.7 Comparison of fusion proteins involving tyrosine kinase proteins in myeloid malignancies
Each fusion protein includes an oligomerization domain plus a tyrosine kinase domain. Breakpoints are indicated by an arrow. HLH, helix-loop-helix domain; TM, transmembrane domain. Reproduced from Bench et al. (2001) with permission from Elsevier Science.
Zn fingers Proline-rich ^
Coiled-coil to the RAS signaling pathway. In common with BCR-ABL and TEL-PDGFRB, ZNF198-FGFR1 possesses transforming ability.
Balanced translocations are rare in 'true' MPD (PV, ET, IMF), although a small number have been reported. Such rare events may mark the site of pathogenetically important genes, the identification of which could offer short cuts to the understanding of the molecular pathogenesis of MPD.
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