Identification and functional characterization of imatinib-sensitive DTD1-PDGFRB and CCDC88C-PDGFRB fusion genes in eosinophilia-associated myeloid/lymphoid neoplasms.
Eosinophilia-associated myeloid neoplasms with rearrangement of chromosome bands 5q31-33 are frequently associated with PDGFRB fusion genes, which are exquisitely sensitive to treatment with imatinib. In search for novel fusion partners of PDGFRB, we analyzed three cases with translocation t(5;20)(q33;p11), t(5;14)(q33;q32), and t(5;17;14)(q33;q11;q32) by 5′-rapid amplification of cDNA ends polymerase chain reaction (5′-RACE-PCR) and DNA-based long-distance inverse PCR (LDI-PCR) with primers derived from PDGFRB. LDI-PCR revealed a fusion between CCDC88C exon 25 and PDGFRB exon 11 in the case with t(5;17;14)(q33;q11;q32) while 5′-RACE-PCR identified fusions between CCDC88C exon 10 and PDGFRB exon 12 and between DTD1 exon 4 and PDGFRB exon 12 in the cases with t(5;14)(q33;q32) and t(5;20)(q33;p11), respectively. The PDGFRB tyrosine-kinase domain is predicted to be retained in all three fusion proteins. The partner proteins contained coiled-coil domains or other domains, which putatively lead to constitutive activation of the PDGFRB fusion protein. In vitro functional analyses confirmed transforming activity and imatinib-sensitivity of the fusion proteins. All three patients achieved rapid and durable complete hematologic remissions on imatinib.
Darko
D
Gosenca
Beate
B
Kellert
Georgia
G
Metzgeroth
Claudia
C
Haferlach
Alice
A
Fabarius
Juliana
J
Schwaab
Michael
M
Kneba
Christof
C
Scheid
Karin
K
Töpelt
Philipp
P
Erben
Torsten
T
Haferlach
Nicholas C P
NC
Cross
Wolf-Karsten
WK
Hofmann
Wolfgang
W
Seifarth
Andreas
A
Reiter
D000328:Adult; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004802:Eosinophilia / Q000188:drug therapy / Q000235:genetics*; D050939:Gene Fusion; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D012074:Remission Induction; D014178:Translocation, Genetic
D000970:Antineoplastic Agents; D001549:Benzamides; C580811:CCDC88C protein, human; D004268:DNA-Binding Proteins; C500359:DTD1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta