T/myeloid mixed phenotype acute leukaemia harbouring TLX3::BCL11B with TLX3 activation

Summary T/myeloid mixed phenotype acute leukaemia (MPAL) is a rare aggressive acute leukaemia with poorly understood pathogenesis. Herein, we report two cases of T/myeloid MPAL harbouring BCL11B‐associated structural variants that activate TLX3 (TLX3::BCL11B‐TLX3‐activation) by genome sequencing and transcriptomic analyses. Both patients were young males with extramedullary involvement. Cooperative gene alterations characteristic of T/myeloid MPAL and T‐lymphoblastic leukaemia (T‐ALL) were detected. Both patients achieved initial remission following lineage‐matched ALL‐based therapy with one patient requiring a lineage‐switched myeloid‐based therapy. Our study is the first to demonstrate the clinicopathological and genomic features of TLX3::BCL11B‐TLX3‐activated T/myeloid MPAL and provide insights into leukaemogenesis.