Haematologica, Vol 92, Issue 2, 163-169 doi:10.3324/haematol.10980
Copyright © 2007 by Ferrata Storti Foundation

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Chronic Myelod Leukemia

Characterization of three new imatinib-responsive fusion genes in chronic myeloproliferative disorders generated by disruption of the platelet-derived growth factor receptor ß gene

Christoph Walz, Georgia Metzgeroth, Claudia Haferlach, Annette Schmitt-Graeff, Alice Fabarius, Volker Hagen, Otto Prümmer, Stefan Rauh, Rüdiger Hehlmann, Andreas Hochhaus, Nicholas C.P. Cross, Andreas Reiter

From the III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany (CW, GM, AF, RH, AH, AR); MLL Münchner Leukämie Labor, München, Germany (CH); Pathologisches Institut, Universitätsklinikum Freiburg, Freiburg, Germany (AS-G); Klinik für Innere Medizin II, St.-Johannes Hospital, Dortmund, Germany (VH); Innere Medizin III, Klinikum Kempten-Oberallgäu, Kempten, Germany (OP); Médecine interne, Hospital Princesse Marie-Astrid, Niederkorn, Grand-Duche-Du Luxembourg (SR); Wessex Regional Genetics Laboratory, Salisbury & Human Genetics Division, University of Southampton, Salisbury, UK (NCPC)

Correspondence: Andreas Reiter, M.D. III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11 68305 Mannheim, Germany. E-mail: andreas.reiter{at}med3.ma.uni-heidelberg. de

Background and Objectives: We sought to identify new fusion genes with involvement of the platelet-derived growth factor receptor ß gene (PDGFRB) in three patients presenting with various subtypes of chronic myeloproliferative disorders associated with chromosomal aberrations involving chromosome bands 5q31–33.

Design and Methods: We performed 5' rapid amplification of cDNA ends (5'-RACE)-polymerase chain reaction (PCR) with RNA/cDNA derived from a patient (case #1) with a t(5;12)(q31–33;q24) and a second patient (case #2) with a complex rearrangement involving chromosomes 1, 5 and 11. A newly developed DNA-based ‘longdistance inverse PCR’ (LDI-PCR) was performed on a third patient (case #3) with a t(4;5;5)(q23;q31;q33).

Results: In cases #1 and #2, we identified mRNA fusions between GIT2 exon 12 and GPIAP1 exon 7, respectively, and PDGFRB exon 11. In case #3, LDI-PCR revealed a fusion between PRKG2 exon 5 and a truncated PDGFRB exon 12. The region encoding the catalytic domain of PDGFRß is retained in all three cases, with the partner contributing a coiled-coil domain (GPIAP1, PRKG2) or an ankyrin protein interaction motif (GIT2) that may potentially lead to dimerization and constitutive activation of the fusion proteins. Treatment with imatinib (400 mg/day) has led to sustained complete hematologic remission in all three patients.

Interpretation and Conclusions: These data provide further evidence that numerous partner genes fuse to PDGFRB in BCR-ABL negative chronic myeloproliferative disorders. Although these fusion genes occur rarely, their identification is essential in order to detect patients in whom targeted treatment with tyrosine kinase inhibitors is likely to be successful.

Key words: GPIAP1, GIT2, PRKG2, PDGFRB, imatinib.

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