Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia. Homo sapiens

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangements involving RARA gene - which predominantly comprises t(15;17) leading to formation of PML-RARA fusion - other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations which cooperate with PML-RARA in the pathogenesis of APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, while mutations in other commonly mutated myeloid leukemia genes were rarely detected. The molecular signature of APL relapse is characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large scale activation of gene expression and reduced in vitro differentiation potential.