Data from Enhancer Hijacking Drives Oncogenic <i>BCL11B</i> Expression in Lineage-Ambiguous Stem Cell Leukemia

Abstract

<div>Abstract<p>Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of <i>BCL11B</i>, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose <i>BCL11B</i> to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to <i>BCL11B</i>. Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed <i>BCL11B</i> allele and association of <i>BCL11B</i> with activated hematopoietic progenitor cell <i>cis</i>-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic <i>BCL11B</i> expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia.</p>Significance:<p>Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of <i>BCL11B</i> driven by diverse structural alterations, including <i>de novo</i> superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries.</p><p><i>This article is highlighted in the In This Issue feature, p. 2659</i></p></div>