Rearrangements and amplification of the ABL1 gene as an example of kinase activation in T-cell acute lymphoblastic
(2008)
Files
Thesis-CGraux-211208.pdf
Open Access - Adobe PDF
- 2.73 MB
Details
- Authors
- Supervisors
- Abstract
- (en) T-cell acute lymphoblastic leukemia (T-ALL) is a neoplastic disorder that develops from a single hematopoietic T-cell precursor that acquired oncogenic anomalies. T-ALL is a heterogeneous disease comprising several clinico-biological entities characterized by distinct underlying genetic defects. In the first part of this work, we attempted to correlate those numerous anomalies with the role of the corresponding non mutated genes or pathways in normal T-cell development. Mutations targeting self-renewal, differentiation, proliferation, survival and death signals cooperate in a multistep process leading to a clinically overt leukemia. Starting from the fortuitous observation by FISH of ABL1 gene amplification in one T-ALL case, we found a new fusion gene, NUP214-ABL1, on amplified episomes in 6% of T-ALL, encoding a constitutively activated chimeric tyrosine kinase. Sensitivity of this oncogenic protein to the tyrosine kinase inhibitor (TKI) imatinib was demonstrated in the T-ALL cell line ALL-SIL carrying the NUP214-ABL1 transcript. Using cytogenetic and molecular analyses, we focused mainly our experimental work on kinase alterations. This class of mutations confers a proliferation advantage to the cell and is frequently observed in cancer, but was only rarely described in T-ALL. The recurrent cryptic NUP214-ABL1 fusion was always amplified, usually extrachromosomally on episomes and/or intrachromosomally in homogeneous staining regions (hsr). In some T-ALL cases both episomes and hsr coexisted. In addition, the NUP214-ABL1 rearrangement was usually associated with other genetic abnormalities, i.e. increased TLX1 or TLX3 expression, deletion of the tumor suppressor gene p16 and mutations of NOTCH1, consistent with a multistep pathogenesis of leukemia. The NUP214-ABL1 fusion gene was sometimes only present in a fraction of the leukemic cells (i.e. in subclones), suggesting its relatively late occurrence. We next investigated whether other ABL1 fusions were involved in T-ALL. We identified EML1-ABL1 in a single T-ALL case as a fusion gene also encoding a constitutively activated tyrosine kinase sensitive to imatinib. Again, coexistence with TLX1, p16 and NOTCH1 anomalies was detected. At disease relapse, a transition from EML1-ABL1 to NUP214-ABL1 positivity was observed. However, retrospective screening for TLX1 and p16 demonstrated that aberrations of these genes persisted at the time of hematological remission. This observation suggested that a latent preleukemic clone with a restricted number of mutations evolved to an aggressive clone with the acquisition of EML1-ABL1, defied chemotherapy, and eventually caused relapse after having acquired another kinase mutation, i.e. NUP214-ABL1. Finally, we explored other tyrosine kinase aberrations in T-ALL by performing genome wide array-CGH screening of copy number abnormalities in T-ALL cell lines. We identified and characterized a new transcript in T-ALL cell-lines and T-ALL patients. In conclusion, this work demonstrates a pathological role of ABL1 fusion variants in T-ALL. For NUP214-ABL1, episomes represent a new mechanism of formation of a fusion. If we consider targeted therapy and the use of TKI (active in vitro) for the treatment of T-ALL we should take into account some T-ALL specificities. Firstly, episomes, when present, are an intrinsic mechanism of drug resistance by virtue of their amplification potential. Secondly, ABL1 fusions (EML1-ABL1 and NUP214-ABL1) represent secondary cooperating events, which suggest that therapy targeting these ABL1 fusion proteins should be given in addition to drugs effective against the associated mutations.
- Affiliations
Citations
Grau, C. (2008). Rearrangements and amplification of the ABL1 gene as an example of kinase activation in T-cell acute lymphoblastic. https://hdl.handle.net/2078.5/129961