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

Abstract

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 ...

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…Three recurrent gene mutations (RUNX1, ASXL1, and TP53) have been added in the risk stratification of the ELN-2017 recommendations for AML [2]. Recently, more novel fusion genes, such as GTF2I-PDGFRB and IKZF1-TYW1 fusion genes, and PAN2/PAN3 complex, have reported and may be clinically important [120,121]. As the new technology advances, more recurrent gene mutations will be explored and used for AML risk stratification and treatment guidelines.…”

Systematic use of fluorescence in‐situ hybridisation and clinicopathological features in the screening of PDGFRB rearrangements of patients with myeloid/lymphoid neoplasms

“…With increased recognition of cryptic PDGFRB rearrangements and the associated exquisite sensitivity to TKI therapy, 12,14–16 it has become necessary to screen cases for this abnormality with methods beyond conventional karyotyping. RNA sequencing is a sensitive method for detecting PDGFRB rearrangements; however, it is not readily available in most clinical laboratories.…”

“…To date, >40 fusion partners of PDGFRB have been reported, with t(5;12)(q33;p13)/ ETV6 – PDGFRB being the most common 8–14 . The disease is usually suspected in the presence of a rearrangement involving chromosome 5q31–33 on conventional karyotyping, which can be confirmed with fluorescence in‐situ hybridisation (FISH) studies to assess involvement of PDGFRB .…”

“…This approach is based on the assumption that rearrangements involving 5q31–33 are visible on analysis of ≥20 metaphases. However, cases with cryptic fusions have been increasingly recognised 12,14–16 . Furthermore, translocations involving 5q31–33 could be missed within a highly complex karyotype 17,18 .…”

Epididymal protein 3A is upregulated and promotes cell proliferation in non‑small cell lung cancer

“…Moreover, double homeobox A pseudogene 10, located in chr14q11.2, promotes an aggressive phenotype by binding lysine-specific histone demethylase 1 and repressing large tumor suppressor kinase 2 and Ras-related glycolysis inhibitor and calcium channel regulator expression levels in NSCLC (17). Furthermore, previous studies have revealed that chr14q11.2 may participate in cancer development (18)(19)(20).…”