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

  • Author(s): Hu, Yeguang
  • Zhang, Zhihong
  • Kashiwagi, Mariko
  • Yoshida, Toshimi
  • Joshi, Ila
  • Jena, Nilamani
  • Somasundaram, Rajesh
  • Emmanuel, Akinola Olumide
  • Sigvardsson, Mikael
  • Fitamant, Julien
  • El-Bardeesy, Nabeel
  • Gounari, Fotini
  • Van Etten, Richard A
  • Georgopoulos, Katia
  • et al.
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.

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