Use of gene expression profiling to identify novel relapse markers in children with high risk acute lymphoblastic leukemia through an international collaboration

Over the years, there have been steady improvements in the management of acute lymphoblastic leukemia in pediatrics [ALL] worldwide, which resulted in a better outcome of the disease. However, 35% of patients relapse while on current therapies. Examining gene expression profiles [GEP] may be the key to further improvement to outcome and decrease the incidence of relapse. This study was done using a novel and unique combination of sophisticated techniques. These are suppression subtractive hybridization [SSH], cDNA concatenated sequencing [CCS] and reverse transcriptase real-time quantitative polymerase chain reaction [RT-RQ-PCR]. This combination allows for the harness of differentially expressed genes, high-throughput sequencing ability and quantitative examination of the expression levels for the differentially expressed sequences respectively, The study focuses on examining differentially expressed genes and potential GEPs for high risk, relapsed and non-relapsed ALL cases with non-determined translocation [NDCT], by performing an SSH on bone marrow samples. The study also aims at providing training in molecular oncology, and transfer of advanced technical and analytical skills from developed to developing countries. Eight genes were found to be differentially expressed between relapsed versus non-relapsed NDCT ALL patients. Seven genes were over expressed in the non-relapsed patients, namely, HNK-Tryp2, TAX, PLSCR, TOP2-B, SP1-2, COP and CASK. Most of these genes have been expressed during cell activation, apoptosis and cancer transformation. Topoisomerase [DNA] II beta [TOP2B] gene functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Only one gene, FLT-3, was found to be constantly more expressed in NDCT ALL children who have relapsed. This study, to the best of our knowledge, is the first to demonstrate that over expression of FLT3 in pediatric high risk NDCT ALL, is associated with relapse. FLT3 suppression with a specific tyrosine kinase inhibitor may be tried as a new therapeutic agent in patients with relapsed ALL