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

• Published in: Genes & development 2016-09, Vol.30 (17), p.1971-1990
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - genetics; Enhancer Elements, Genetic - physiology; Epigenesis, Genetic; Epithelial Cells - cytology; Epithelial Cells - pathology; Gene Expression Regulation, Leukemic; Ikaros Transcription Factor - genetics; Ikaros Transcription Factor - metabolism; Mice; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - physiopathology; Precursor Cells, B-Lymphoid - cytology; Precursor Cells, B-Lymphoid - pathology; Research Paper; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0890-9369; 1549-5477; 1549-5477
• DOI: 10.1101/gad.283762.116

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.