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Case Reports
. 2020 Apr 3;13(1):58.
doi: 10.1186/s12920-020-0709-y.

Comprehensive chromosomal aberrations in a case of a patient with TCF3-HLF-positive BCP-ALL

Monika Lejman  1 , Monika Włodarczyk  2 , Joanna Zawitkowska  3 , Jerzy R Kowalczyk  3
Affiliations
Case Reports

Comprehensive chromosomal aberrations in a case of a patient with TCF3-HLF-positive BCP-ALL

Monika Lejman et al. BMC Med Genomics. .

Abstract

Background: The use of high-throughput analytical techniques has enabled the description of acute lymphoblastic leukaemia (ALL) subtypes. The TCF3-HLF translocation is a very rare rearrangement in ALL that is associated with an extremely poor prognosis. The TCF3-HLF fusion gene in the described case resulted in the fusion of the homeobox-related gene of TCF3 to the leucine zipper domain of HLF. The TCF3-HLF fusion gene product acts as a transcriptional factor leading to the dedifferentiation of mature B lymphocytes into an immature state (lymphoid stem cells). This process initiates the formation of pre-leukaemic cells. Due to the rarity of this chromosomal aberration, only a few cases have been described in the literature. The advantage of this work is the presentation of an interesting case of clonal evolution of cancer cells and the cumulative implications (diagnostic and prognostic) of the patient's genetic alterations.

Case presentation: This work presents a patient with diagnosed with TCF3-HLF-positive ALL. Moreover, the additional genetic alterations, which play a key role in the pathogenesis of ALL, were detected in this patient: deletion of a fragment from the long arm of chromosome 13 (13q12.2-q21.1) containing the RB1 gene, intragenic deletions within the PAX5 gene and NOTCH1 intragenic duplication.

Conclusions: A patient with coexistence of chromosomal alterations and the TCF3-HLF fusion has not yet been described. Identifying all these chromosomal aberrations at the time of diagnosis could be sufficient to determine the cumulative effects of the described deletions on the activity of other oncogenes or tumour suppressors, as well as on the clinical course of the disease. On the other hand, complex changes in the patient's karyotype and clonal evolution of cancer cells call into question the effectiveness of experimental therapy.

Keywords: Acute lymphoblastic leukaemia; Case report; Gene fusion; Molecular abnormalities; RB1; TCF3-HLF.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Cytogenetic features at diagnosis. a GTG band staining study of the patient revealed 46,XX. b, c, d Results of FISH tests with BCR/ABL1, KMT2A and ETV6/RUNX1 probes. FISH was performed on interphase nuclei using probes (Cytocell Ltd., Oxford Gene Technology, Cambridge, United Kingdom) according to the manufacturer’s recommendations. Images were captured by an Olympus BX41TF microscope equipped with a Jenoptik camera and analysed with Isis Software (MetaSystems)
Fig. 2
Fig. 2
Cytogenetic features at diagnosis and relapse. a Image of the FISH results with the BCR/ABL1 probe revealing an additional green signal from the BCR locus on chromosome 22. Images of metaphases FISH with the TCF3/PBX/HLF probe in samples from diagnosis (b) and relapse (c). Image of interphase FISH with CCP13/CCP21 probe in samples from diagnosis (d) revealing a lack of 13q deletion genes: MED4, ITM2B, RB1, RCBTB2, and CYSLTR2). FISH was performed on cells in metaphase using probes (Cytocell Ltd., Oxford Gene Technology, Cambridge, United Kingdom) according to the manufacturer’s recommendations. Images were captured by an Olympus BX41TF microscope equipped with a Jenoptik camera and analysed with Isis Software (MetaSystems)
Fig. 3
Fig. 3
Karyoviews from microarray results at the time of diagnosis and relapse. a Microarray results revealing a deletion of fragment of the long arm of chromosome 13 (13q12.2-q21.1) containing the RB1 gene (red box), PAX5 intragenic deletion and NOTCH1 intragenic duplication (both on chromosome 9). b Microarray results revealing that 13q deletion was not found in samples from relapse. In addition to the PAX5 and NOTCH1 alterations, CDKN2A/B deletion (red box) and 22 trisomy (blue box) were also observed. Asterisks correspond to deletion (red colour), duplication (blue colour) and loss of heterozygosity (purple colour)
Fig. 4
Fig. 4
The schemes around the breakpoints of two different types of TCF3-HLF fusion transcripts are depicted. Two breakpoints clustering in two TCF3 intronic regions are distinguished. At the transcript level, type I translocation results in joining TCF3 exon 16 to HLF exon 4. Moreover, intronic sequences, new splice sites and inserted non-template sequences are attached to the HLF gene (purple shadowed line). Implications resulting from the insertion of certain sequences have not yet been studied. Type II translocation occurs downstream of TCF3 exon 15. In this case, TCF3 exon 16 is not part of the fusion transcript. Boxes correspond to exonic regions of the TCF3 gene (green) and the HLF gene (red). Lines correspond to intronic regions of the TCF3 gene (green) and the HLF gene (red). Additional upstream and downstream exons of the TCF3 and HLF gene are not graphically represented (broken coloured lines). Lightning bolts represent intronic breakpoints
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