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Institute of Pathology
Researchers have identified genetic mutations that contribute to the onset of acute promyelocytic leukemia (APL), according to a paper published in Leukemia.
The team analyzed patient samples to identify somatic mutations that cooperate with the PML-RARA fusion gene in the pathogenesis of APL.
They performed whole-exome and targeted sequencing on 242 samples from APL patients, 165 who were newly diagnosed and 77 who had relapsed.
Samples from patients with newly diagnosed APL had recurrent mutations in FLT3, WT1, NRAS, and KRAS but rarely had mutations in other genes commonly mutated in myeloid leukemia.
The newly diagnosed samples also had loss-of-function mutations in ARID1A and ARID1B (members of a chromatin remodeling complex), which had not previously been identified in APL.
The researchers said the ARID1A and ARID1B mutations indicate dysregulation of epigenetic machinery in APL, and the mutations provide a subset of previously uncharacterized genes in leukemogenesis.
The team also found that knocking down ARID1B in the APL cell line NB4 resulted in large-scale activation of gene expression and reduced in vitro differentiation potential.
In the relapsed APL samples, the researchers discovered a set of mutations that were not observed in the newly diagnosed samples. Most prominently, mutations in RARA and PML were found to be exclusive to relapsed samples.
The team also found these mutations were largely acquired in 2 distinct patient groups—those treated at initial diagnosis with all-trans retinoic acid and those treated with arsenic trioxide.
“Our comprehensive study on the mutational landscape in a large cohort of primary and relapsed APL cases has enabled us to establish the molecular roadmap for APL, which is distinct from other subtypes of [acute myeloid leukemia],” said study author H. Phillip Koeffler, MD, of the Cancer Science Institute of Singapore.
“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.”
