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首页> 外文期刊>Experimental Hematology Oncology >Novel GTF2I–PDGFRB and IKZF1–TYW1 fusions in pediatric leukemia with normal karyotype
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Novel GTF2I–PDGFRB and IKZF1–TYW1 fusions in pediatric leukemia with normal karyotype

机译：小型GTF2I-PDGFRB和IKZF1-TYW1具有正常核型儿科白血病的融合

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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. 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. 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.
机译：许多急性淋巴细胞白血病（全部）携带可见的染色体变化，致病，诊断和预后重要性。然而，从新诊断的四分之一到一半患者诊断时G型染色分析可检测到所有患者的所有患者的可见染色体变化。强大的分子方法的引入表明，许多核型正常均均携带临床重要的亚微米畸形。我们使用荧光原位杂交（鱼），阵列对比基因组杂交（ACGH），RNA测序，逆转录（RT）和基因组聚合酶链式反应（PCR），以及桑切尔测序，以调查小儿的案例核型。具有商业PDGFRB Breakapart探测的鱼显示探针的远端部分的损失，表明PDGFRB基因座内的断点。 Acgh透露染色体带5q32Q35.3的亚型缺失（长约30μmb，在PDGFRB中开始，在CANX基因座内完成），7Q4（TCRB内），9p13（PAX5），10Q26.13（DMBT1），14Q11.2（ TRAC）和14Q32.33（在IGH轨迹内）。 RNA测序检测到框架内的GTF2I-PDGFRB和框架外IKZF1-TYW1融合转录物。将融合转录物均通过RT-PCR核实，并将其与Sanger测序和互相鱼核实。 GTF2I-PDGFRB融合也被基因组PCR和鱼核实。相应的GTF2I-PDGFRB融合蛋白将包括几乎整个GTF2I和PDGFRB的那部分，其终止酪氨酸激酶的催化结构域。因此，它似乎导致酪氨酸激酶活性异常，类似于其他PDGFRB融合蛋白所见的方式。所检查的儿科白血病是一种pH样，携带新的GTF2I-PDGFRB和IKZF1-TYW1融合基因以及额外的亚微血症缺失。因为具有PDGFRB-融合基因的血液学肿瘤可以用酪氨酸激酶抑制剂治疗，所以这种新融合的检测可能是临床重要的。由于仅在白血病细胞的分子研究之后可以检测到GTF2I-PDGFRB，因此需要进一步研究所有情况，也许特别但不完全具有正常的核型，以确定白血病中GTF2I-PDGFRB的频率，以及还要找出融合可能具有的临床影响。

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