liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
Superenhancer reprogramming drives a B-cell-epithelial transition and high-risk leukemia
Harvard Medical Sch, MA 02129 USA.
Harvard Medical Sch, MA 02129 USA.
Harvard Medical Sch, MA 02129 USA.
Harvard Medical Sch, MA 02129 USA.
Show others and affiliations
2016 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 30, no 17, 1971-1990 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT , 2016. Vol. 30, no 17, 1971-1990 p.
Keyword [en]
TEAD; YAP1; LHX2; PRC2; self-renewal
National Category
Developmental Biology
URN: urn:nbn:se:liu:diva-132482DOI: 10.1101/gad.283762.116ISI: 000384964600008PubMedID: 27664237OAI: diva2:1046264

Funding Agencies|National Institutes of Health [R01CA162092, R21AI124326, R01CA090576, R01CA190964]

Available from: 2016-11-13 Created: 2016-11-12 Last updated: 2016-12-02

Open Access in DiVA

fulltext(2956 kB)17 downloads
File information
File name FULLTEXT01.pdfFile size 2956 kBChecksum SHA-512
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Somasundaram, RajeshSigvardsson, Mikael
By organisation
Division of Microbiology and Molecular MedicineFaculty of Medicine and Health Sciences
In the same journal
Genes & Development
Developmental Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 17 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 23 hits
ReferencesLink to record
Permanent link

Direct link