Acute leukemia with BCL11B rearrangements: Genetic landscape, BCL11B expression, and therapeutic response

Rearrangements involving BCL11B have emerged as important structural variants in acute leukemias with T lineage differentiation, yet their prevalence and biological significance remain incompletely defined. Using optical genome mapping (OGM), we identified BCL11B rearrangements in 25 of 2325 hematologic malignancies, restricted to T-lymphoblastic leukemia particularly early T precursor (ETP) subtype, mixed phenotype acute leukemia T/myeloid, and rare acute myeloid leukemia. Breakpoints at 14q32.2 were highly variable and largely cryptic by karyotyping. Twelve putative partner genes were detected, including four previously reported (TLX3, ARID1B, CDK6, and CCDC26) and 8 novel partners (FOXF1, TLX1, NUP98, LMO2, GAPDHP71, GRM4, TNFAIP3, and TRRAP). Evaluation of BCL11B expression showed that rearrangements involving partners currently considered "BCL11B-activated", such as ARID1B, CCDC26, and CDK6, did not uniformly associate with BCL11B overexpression. Conversely, cases with TLX3::BCL11B, previously thought to upregulate TLX3, demonstrated strong BCL11B expression (3 of 4 cases). Clinically, newly diagnosed patients, most treated with venetoclax based regimens, achieved high remission rates. Our data delineate the structural diversity of BCL11B rearrangements identified by OGM and show that BCL11B activation cannot be reliably inferred from partner gene identity alone. BCL11B immunohistochemistry as a practical surrogate for assessing BCL11B activation is recommended in routine practice.