Scientists identify new genetic variations contributing to the development of the PLA -
NUS study finds new genetic alterations contribute to the development of leukemia
the results of the international study involving 220 samples of newly diagnosed patients and relapsed pave the way for the development of new therapies
a study by a team of scientists from the Institute of cancer sciences Singapore (Singapore CSI) at the national University of Singapore (NUS) has identified new genetic alterations that contribute to the onset of acute promyelocytic leukemia (APL). APL is a subtype of acute myeloid leukemia (AML), where there is an abnormal accumulation of immature white blood cells called promyelocytes.
The team, led by Professor Phillip H. Koeffler, senior principal researcher at CSI Singapore, conducted a study to discover the mutational landscape of the PLA, both the primary disease and post-treatment relapses. This study, international collaboration and also the largest of its kind to date, involved 220 patient samples from newly diagnosed and relapsed APL countries such as Singapore, Germany, India, the US and Taiwan.
The results of the study, published online in the journal Leukemia in April 2016, will pave the way for improved diagnosis and treatment of APL.
mutations in new cases and relapse APL
Dr Vikas Madan, a researcher at CSI Singapore and first author of the study said: "Patients usually respond to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapy, which is the preferred treatment method for APL. However, a considerable proportion of patients either do not respond to treatment or relapse after standard treatment. although chromosomal damage leading to the fusion of PML and RARA gene is a genetic event well known in APL, studies have also suggested that other genetic abnormalities and PML -RARA oncogene, also contribute to the development of the PLA. Thus, discovering the complete molecular profile of the disease will be invaluable. "
Currently, most genomic studies on AML only focused on new cases, and few studies have been conducted on APL. The study team consisted of two newly diagnosed cases and APL relapse to identify mutations driver that arise in the post-treatment relapse in order to gain a better understanding of the progression of the disease.
team identified several genetic mutations in secondary new cases of APL, including new mutations identified in APL. specifically, the study team showed mutations in ARID1A genes and ARID1B, who are members of a chromatin remodeling complex to the first time. mutations of these closely related members indicate dysregulation of epigenetic machinery in APL and these new mutations provide a subset of genes previously uncharacterized in leukemogenesis.
in case of relapse, the team also discovered a different set of genetic changes that are not observed in newly diagnosed cases. Most prominently, the mutation of PML and RARA genes were found to be exclusive to relapse cases. Strikingly, the study also showed that these changes were largely acquired in two separate groups of patients, those treated at initial diagnosis with ATRA and ATO-based therapy, respectively.
"Our detailed study of the mutational landscape in a large primary APL cases and relapse cohort allowed us to establish the molecular roadmap for APL, which is distinguished from other subtypes of AML. with better knowledge of the biology of the disease, we will conduct further research to discover the consequences of new mutations discovered, with a final aim to develop improved and targeted therapeutic products, "said Professor Koeffler.
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