Page 93 - Read Online

Othman et al. J Cancer Metastasis Treat 2018;4:50 I http://dx.doi.org/10.20517/2394-4722.2018.41 Page 7 of 9

that they could be considered as identical diseases in the future [1,4,12,14,15,21-24] .

As shown in our case, NUP214-ABL1 is accompanied with loss of cyclin-dependent kinase inhibitor 2A
(CDKN2A), which encodes the tumorsuppressors p16INK4A and p14ARF, and affects cell cycle progression.
CDKN2A gene deletion can be detected at initial diagnosis or acquired at relapse, suggesting that CDKN2A
gene deletion is a secondary genetic event and associated with chromosomal rearrangements. This may as a
result lead to the aberrant expression of a diverse group of T-cell-specific transcription factors, which again
can function as oncogenes, such as TLX1 and TLX3 [2,21,25] . The translocation t(7;10)(q34;q24), resulting from
the TRB/TLX1 fusion gene, has been reported in several studies, and is present in 5% of pediatric and 30% of
adult with T-cell ALL [25-28] .

Overall, in the present T-LBL case we identified substantial intra-tumor genetic heterogeneity and complex-
ity. The founder clone has TRB/TLX1 fusion gene and the subclone has TRB/TLX1 fusion gene plus complex
karyotype involving three-way translocation t(2;7;10)(2q37.3;7q34;10q25.1), further developing into a more
complex subclone. Interestingly, the breakpoints at 2q37.3, 7q34, 10q24.3 and 10q25.1 were not previously
[29]
reported in T-LBL . Thus, this data provides genetic support for a multi-step pathogenesis: deletion of a
tumor-suppressor gene (CDKN2A), deregulated expression of a transcription factor TLX1 and most likely
overexpression of a constitutively activated tyrosine kinase (NUP214-ABL1) and oncogene c-MYB due to epi-
some amplification and the unique phenotypes of the T-LBL case mentioned above.

To conclude, this study demonstrates the power of high resolution molecular approaches. It may be consid-
ered that the use of such approaches is the most efficient and future standard method for screening ABL1
alteration. Particularly in T-LBL patients this may be advantageous, as ABL1 modulates T-cell development
and plays a role in cytoskeletal remodeling processes in T-cells. Besides, the intra-tumor genetic heterogene-
ity in cancer has important implications for reservoirs of cells involved in progression of disease and drug
resistance therapy. As NUP214-ABL1 fusion is sensitive to the tyrosine kinase inhibitor, this suggests that
new therapeutic approaches in T-LBL may improve outcome and/or decrease treatment-related morbidity.

DECLARATIONS
Authors’ contributions

Did the FISH-studies and drafted the paper: OthmanMAK
Performed array comparative genomic hybridization (aCGH) analyses and interpretation: MeloJB, Carreira

IM, OthmanMAK
Provided T-LBL-case including clinical and banding cytogenetic data: GrygalewiczB, Kołkowska-LeśniakA

Planned and organized the study and did final drafting of the paper: Liehr T
All authors read and approved the paper.
Availability of data and materials
[30]
All data is provided in this article. Also the patient was mentioned previously in as P61.
Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
The present study was approved by the Ethical Board at the Friedrich Schiller University (Jena, Germany;
approval No., 1105-04/03). Consent to participate of the parent of the patient studied here is available on re-
quest from the authors of this paper.