Subscribe: pubmed: Curr Op Hem[Jour]
http://eutils.ncbi.nlm.nih.gov/entrez/eutils/erss.cgi?rss_guid=0qONaGgEKPpr-ByJ9az2-U31ytpT4JzyN9oB_8YYP7j
Preview: pubmed: Curr Op Hem[Jour]

pubmed: Curr Op Hem[Jour]



NCBI: db=pubmed; Term="Current Opinion in Hematology"[Jour]



 



Transcriptional circuits in B cell transformation.
(image) Related Articles

Transcriptional circuits in B cell transformation.

Curr Opin Hematol. 2017 Apr 29;:

Authors: Hu Y, Yoshida T, Georgopoulos K

Abstract
PURPOSE OF REVIEW: Loss of IKAROS in committed B cell precursors causes a block in differentiation while at the same time augments aberrant cellular properties, such as bone marrow stromal adhesion, self-renewal and resistance to glucocorticoid-mediated cell death. B cell acute lymphoblastic leukaemias originating from these early stages of B cell differentiation and associated with IKAROS mutations share a high-risk cellular phenotype suggesting that deregulation of IKAROS-based mechanisms cause a highly malignant disease process.
RECENT STUDIES: Recent studies show that IKAROS is critical for the activity of super-enhancers at genes required for pre-B cell receptor (BCR) signalling and differentiation, working either downstream of or in parallel with B cell master regulators such as EBF1 and PAX5. IKAROS also directly represses a cryptic regulatory network of transcription factors prevalent in mesenchymal and epithelial precursors that includes YAP1, TEAD1/2, LHX2 and LMO2, and their targets, which are not normally expressed in lymphocytes. IKAROS prevents not only expression of these 'extra-lineage' transcription factors but also their cooperation with endogenous B cell master regulators, such as EBF1 and PAX5, leading to the formation of a de novo for lymphocytes super-enhancer network. IKAROS coordinates with the Polycomb repression complex (PRC2) to provide stable repression of associated genes during B cell development. However, induction of regulatory factors normally repressed by IKAROS starts a feed-forward loop that activates de-novo enhancers and elevates them to super-enhancer status, thereby diminishing PRC2 repression and awakening aberrant epithelial-like cell properties in B cell precursors.
SUMMARY: Insight into IKAROS-based transcriptional circuits not only sets new paradigms for cell differentiation but also provides new approaches for classifying and treating high-risk human B-ALL that originates from these early stages of B cell differentiation.

PMID: 28463873 [PubMed - as supplied by publisher]