Lindsey Montefiori, PhD, Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, discusses interesting findings of a transcriptome and genome sequencing study which aimed to better classify subtypes of lineage ambiguous acute leukemia (ALAL). While investigating the genetic profiles of a large pan-acute leukemia cohort, it was found that a third of the ALAL samples had a distinct genetic profile, despite the samples being distinct diagnostic entities, including T/myeloid mixed phenotype acute leukemia (MPAL), T-cell precursor acute lymphoblastic leukemia (EPT-ALL), and acute myeloid leukemia (AML). Structural alterations in the BCL11B transcription factor gene were observed in the cohort, where further analysis using HiChIP deemed the structural alterations places BCL11B under transcriptional control of powerful enhancers that are active in normal stem and progenitor cells. This enhancer hijacking mechanism causes aberrant expression of BCL11B. Dr. Monterfiori then goes on to discuss prospective studies and clinical trials to understand the mechanisms of BCL11B structural abnormalities, which could in the future influence the way leukemia subtypes are classified and treated. This interview took place during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, 2020.