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

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 homeoboxrelated 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.

TCF3 gene rearrangements in pediatric B‐cell acute lymphoblastic leukemia—A single center experience

“…In agreement with these data, two major types of TCF3 rearrangement do not differ in either OS or EFS in our study. TCF3 :: HLF ‐associated BCP‐ALL, however, stands out dramatically in survival rates—EFS was shown to be 25%; this rearrangement is associated with poor response to treatment and early relapse of the disease, even after the patient receives hematopoietic stem cell transplantation 36–38 . Our data is in full agreement with the literature demonstrating statistically significant difference in EFS between TCF3 :: HLF and other types of TCF3 rearrangement ( p = 0.0055).…”

“…TCF3::HLF-associated BCP-ALL, however, stands out dramatically in survival rates-EFS was shown to be 25%; this rearrangement is associated with poor response to treatment and early relapse of the disease, even after the patient receives hematopoietic stem cell transplantation. [36][37][38] Our data is in full agreement with the literature demonstrating statistically significant difference in EFS between TCF3::HLF and other types of TCF3 rearrangement (p = 0.0055). A feasible treatment approach is blinatumomab and stem cell transplantation which lead to durable remissions in this unfavorable type of BCP-ALL.…”

Cryptic TCF3 fusions in childhood leukemia: Detection by RNA sequencing

“…With an observed event‐free 5‐year‐survival of approximately 85%, it is associated with a rather good prognosis 4–7 . As a very rare event, < 1% of the TCF3 alterations in ALL lead to a TCF3‐HLF fusion gene 8–13 . The detection of this fusion gene is associated with a very poor prognosis with incurable relapses in almost all patients 3,14 .…”

“…200-445 Tsd/μl) and a decreased QUICK (55%; ref. 70%-130%).Patient 2 showed a translocation t(5;12)(q35;q13) and a questionable aberration in the long arm of chromosome 11 in seven out of 20 metaphases (ISCN-karyotype: 46,XY,t(5;12)(q35;q13),?add (11)(q24)[7]/46,XY[13]) (Figure1B). The break apart FISH probe for TCF3 showed a split signal indicating a TCF3 translocation in 25% of the interphase nuclei (cutoff: 4%).…”

“…[4][5][6][7] As a very rare event, < 1% of the TCF3 alterations in ALL lead to a TCF3-HLF fusion gene. [8][9][10][11][12][13] The detection of this fusion gene is associated with a very poor prognosis with incurable relapses in almost all patients. 3,14 The TCF3 gene encodes a transcription factor that is essential for B-cell lineage development.…”