Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

Abstract

IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors. IKAROS is also highly enriched at inactive enhancers of genes normally expressed in stem-epithelial cells. Upon IKAROS loss, expression of pre-B-cell differentiation genes is attenuated, while a group of extralineage transcription factors that are directly repressed by IKAROS and depend on EBF1 relocalization at their enhancers for expression is induced. LHX2, LMO2, and TEAD-YAP1, normally kept separate from native B-cell transcription regulators by IKAROS, now cooperate directly with them in a de novo superenhancer network with its own feed-forward transcriptional reinforcement. Induction of de novo superenhancers antagonizes Polycomb repression and superimposes aberrant stem-epithelial cell properties in a B-cell precursor. This dual mechanism of IKAROS regulation promotes differentiation while safeguarding against a hybrid stem-epithelial-B-cell phenotype that underlies high-risk B-ALL.

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

“…2; Heizmann et al 2013;Joshi et al 2014;Schwickert et al 2014). This is not just a block in differentiation but also a dramatic gain in cell adhesion that is manifested not only in vivo but also upon IKAROS deletion in established wild-type pre-B-cell cultures, indicating a continued requirement for IKAROS repression of the mechanisms that support this cellular property (Joshi et al 2014;Hu et al 2016).…”

“…1A). The middle two of the Nterminal zinc finger motifs (F2 and F3) make sequencespecific contacts to DNA through the a/gGGAA core motif that is also recognized by other types of transcription factors, such as ETS, NFκΒ, STAT, RBPj/κ, and TEAD, suggesting a functional interplay between these factors during differentiation Hu et al 2016). The two outer zinc fingers (F1 and F4), although not directly engaged in DNA binding, also contribute to IKAROS activity.…”

“…2; Dias et al 2008). The overlap in deregulated genes between E2A and IKAROS mutant multipotent progenitors and the proximity of IKAROS-and E-box-binding sites on chromatin suggest cooperation between these two families of transcription regulators in setting up the epigenetic blueprint for lymphocyte differentiation (Dias et al 2008;Zhang et al 2011;Hu et al 2016).…”

“…Given the conservation in IKAROS-based transcriptional mechanisms prior to and after B-cell lineage commitment, a study on the IKAROS modus operandi in pre-B cells has provided key insight into the regulation of this developmental process and the origins of high-risk pre-Bcell precursor leukemias (Hu et al 2016). IKAROS chromatin distribution studies in large pre-B cells have revealed that this factor is engaged mostly at enhancer sites classified as active or poised/inactive by their immediate chromatin environment ( Fig.…”

“…IKAROS chromatin distribution studies in large pre-B cells have revealed that this factor is engaged mostly at enhancer sites classified as active or poised/inactive by their immediate chromatin environment ( Fig. 3; Hu et al 2016).…”