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Background  Many cases of acute lymphoblastic leukemia (ALL) carry visible acquired chromosomal changes of pathogenetic, diagnostic, and prognostic importance. Nevertheless, from one-fourth to half of newly diagnosed ALL patients have no visible chromosomal changes detectable by G-banding analysis at diagnosis. The introduction of powerful molecular methodologies has shown that many karyotypically normal ALLs carry clinically important submicroscopic aberrations.    Case presentation  We used fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), RNA sequencing, reverse transcription (RT) and genomic polymerase chain reaction (PCR), as well as Sanger sequencing to investigate a case of pediatric ALL with a normal karyotype. FISH with a commercial  PDGFRB  breakapart probe showed loss of the distal part of the probe suggesting a breakpoint within the  PDGFRB  locus. aCGH revealed submicroscopic deletions in chromosome bands 5q32q35.3 (about 30 Mb long, starting within  PDGFRB  and finishing in the  CANX  locus), 7q34 (within  TCRB ), 9p13 ( PAX5 ), 10q26.13 ( DMBT1 ), 14q11.2 ( TRAC ), and 14q32.33 (within the  IGH  locus). RNA sequencing detected an in-frame  GTF2I – PDGFRB  and an out-of-frame  IKZF1 – TYW1  fusion transcript. Both fusion transcripts were verified by RT-PCR together with Sanger sequencing and interphase FISH. The  GTF2I – PDGFRB  fusion was also verified by genomic PCR and FISH. The corresponding  GTF2I – PDGFRB  fusion protein would consist of almost the entire GTF2I and that part of PDGFRB which harbors the catalytic domain of the tyrosine kinase. It would therefore seem to lead to abnormal tyrosine kinase activity in a manner similar to what has been seen for other PDGFRB fusion proteins.    Conclusions  The examined pediatric leukemia is a Ph-like ALL which carries novel  GTF2I – PDGFRB  and  IKZF1 – TYW1  fusion genes together with additional submicroscopic deletions. Because hematologic neoplasms with  PDGFRB -fusion genes can be treated with tyrosine kinase inhibitors, the detection of such novel fusions may be clinically important. Since the  GTF2I – PDGFRB  could be detected only after molecular studies of the leukemic cells, further investigations of ALL-cases, perhaps especially but not exclusively with a normal karyotype, are needed in order to determine the frequency of  GTF2I – PDGFRB  in leukemia, and also to find out which clinical impact the fusion may have.

Novel GTF2I–PDGFRB and IKZF1–TYW1 fusions in pediatric leukemia with normal karyotype