The PML–RARA fusion is pathognomic in acute promyelocytic leukaemia (APL); however, other mutations have also been implicated in APL pathogenesis. Whole-genome sequencing of 12 primary diagnosis samples and eight matched relapse samples revealed 109 genes harbouring nonsilent mutations. Subsequently, targeted sequencing was performed on these 109 genes, as well as another 289 genes implicated in APL, in 153 primary and 69 relapse samples. Apart from the PML–RARA fusion, the most frequent recurrent alterations in primary AML samples were in FLT3, WT1, NRAS, and KRAS, as well as previously unidentified mutations in the ARID1A and ARID1B genes that both encode components of the SWI–SNF complex. Of note, ARID1B was mutated at a higher frequency at relapse than in primary samples, as were PML, RARA, and RUNX1. These genes are thus implicated in treatment resistance. Results of in vitro experiments suggested that loss of ARID1B impairs treatment-induced cell differentiation.