A study led by a team of scientists from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) has identified new genetic alterations contributing 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 Prof H. Phillip Koeffler, Senior Principal Investigator at CSI Singapore, conducted a study to uncover the mutational landscape of APL, both at primary disease and post-therapy relapse. This study, an international collaboration and also the largest of its kind to date, involved about 220 patient samples from newly-diagnosed and relapse APL cases from countries such as Singapore, Germany, India, United States, and Taiwan.
The findings of the study, first published online in the journal Leukemia in April 2016, will pave the way for improved diagnosis and treatment of APL.
Mutations in new and relapse APL cases
Dr Vikas Madan, Research Scientist at CSI Singapore and first author of the study said, "Patients generally respond well to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapy, which is the preferred mode of treatment for APL. However, a considerable proportion of patients either do not respond to standard therapies or relapse following treatment. While chromosomal alteration leading to fusion of PML and RARA genes is a well-known genetic event in APL, studies have also suggested that other genetic abnormalities, together with PML-RARA oncogene, also contribute to development of APL. Hence, uncovering the complete molecular profile of the disease will be valuable."
Currently, most genomic studies on AML only focused on new cases, and few studies have been conducted on APL. The team's study comprised both newly-diagnosed and relapse APL cases to identify driver mutations which arise in post-therapy relapse in order to gain a better understanding of the disease progression.
The team identified several secondary genetic mutations in new APL cases, including novel mutations identified in APL. Specifically, the team's study showed mutations in genes ARID1A and ARID1B, which are members of a chromatin remodelling complex, for the first time. The mutations of these closely related members indicate dysregulation of epigenetic machinery in APL and these novel mutations provide a subset of previously uncharacterised genes in leukemogenesis.
In relapse cases, the team also discovered a different set of gene alterations which were not observed in newly diagnosed cases. Most prominently, mutation of genes RARA and PML were found to be exclusive to relapse cases. Strikingly, the study also showed that these alterations were largely acquired in two distinct patient groups, those treated at initial diagnosis with ATRA and ATO-based therapy, respectively.
"Our comprehensive study on the mutational landscape in a large cohort of primary and relapse APL cases has enabled us to establish the molecular roadmap for APL, which is distinct from other subtypes of AML. With an enhanced knowledge of the disease biology, we will be conducting further research to uncover the consequences of the novel mutations discovered, with an eventual goal of developing improved and targeted therapeutics," said Prof Koeffler.
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