Characterization of three new imatinib-responsive fusion genes in chronic myeloproliferative disorders generated by disruption of the platelet-derived growth factor receptor beta gene.
OBJECTIVE
We sought to identify new fusion genes with involvement of the platelet-derived growth factor receptor beta gene (PDGFRB) in three patients presenting with various subtypes of chronic myeloproliferative disorders associated with chromosomal aberrations involving chromosome bands 5q31-33.


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 long-distance 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 PDGFRbeta 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.


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.
Walz
Christoph
C
III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11 68305 Mannheim, Germany.
Metzgeroth
Georgia
G
Haferlach
Claudia
C
Schmitt-Graeff
Annette
A
Fabarius
Alice
A
Hagen
Volker
V
Prümmer
Otto
O
Rauh
Stefan
S
Hehlmann
Rüdiger
R
Hochhaus
Andreas
A
Cross
Nicholas C P
NC
Reiter
Andreas
A
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D018797:Cell Cycle Proteins; D002869:Chromosome Aberrations; D002871:Chromosome Banding; D002895:Chromosomes, Human, Pair 5; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic
D000970:Antineoplastic Agents; D001549:Benzamides; C486562:CAPRIN1 protein, human; D018797:Cell Cycle Proteins; C430213:GIT2 protein, human; D020690:GTPase-Activating Proteins; D010879:Piperazines; D011743:Pyrimidines; D014157:Transcription Factors; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta