ETV6 Rearrangement Suppresses CDKN1B Transcription by Disrupting an Intragenic Super-Enhancer in Acute Lymphoblastic Leukemia.

ETV6-rearranged acute lymphoblastic leukemia (ALL) is associated with poor prognosis in adults. Previously, a super-enhancer (SE) located within the ETV6 intragenic region (ETV6-SE) was identified in a rare fusion gene, ETV6::ACSL6, but further work is needed to determine whether ETV6-SE is broadly present in ALL and how ETV6 rearrangements impact the SE function. Here, we demonstrated that ETV6 functions as a regulatory element via ETV6-SE in ALL, with CDKN1B as a key target. CRISPR interference and knockout experiments revealed the core enhancer region within ETV6-SE responsible for CDKN1B regulation. ETV6 rearrangements disrupted ETV6-SE and impaired long-range chromatin interaction with the CDKN1B locus, leading to its downregulation that in turn activated the NF-κB pathway and increased expression of anti-apoptotic proteins BCL-2/BCL-XL. In patient-derived xenograft (PDX) models, pharmacological inhibition of BCL-2/BCL-XL using venetoclax or navitoclax showed additive effects when combined with dexamethasone. Collectively, these findings establish the ETV6-SE-CDKN1B regulatory axis as a mechanism contributing to treatment resistance in ETV6-rearranged ALL.