Transcriptional Circuits in B Cell Transformation

Overview

Journal Curr Opin Hematol

Specialty Hematology

Date 2017 May 3

PMID 28463873

Citations 12

Authors

Yeguang Hu

Toshimi Yoshida

Katia Georgopoulos

Affiliations

Soon will be listed here.

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.

Citing Articles

ANP32B suppresses B-cell acute lymphoblastic leukemia through activation of PU.1 in mice.

Yang Q, Liu H, Yang S, Wei Y, Zhu X, Zhi Z Cancer Sci. 2023; 114(7):2882-2894.

PMID: 37137487 PMC: 10323103. DOI: 10.1111/cas.15822.

Infectious triggers and novel therapeutic opportunities in childhood B cell leukaemia.

Cobaleda C, Vicente-Duenas C, Sanchez-Garcia I Nat Rev Immunol. 2021; 21(9):570-581.

PMID: 33558682 DOI: 10.1038/s41577-021-00505-2.

Cell Fate Decisions: The Role of Transcription Factors in Early B-cell Development and Leukemia.

Fischer U, Yang J, Ikawa T, Hein D, Vicente-Duenas C, Borkhardt A Blood Cancer Discov. 2021; 1(3):224-233.

PMID: 33392513 PMC: 7774874. DOI: 10.1158/2643-3230.BCD-20-0011.

Established and emergent roles for Ikaros transcription factors in lymphoid cell development and function.

Read K, Jones D, Freud A, Oestreich K Immunol Rev. 2020; 300(1):82-99.

PMID: 33331000 PMC: 8015388. DOI: 10.1111/imr.12936.

A transcriptome-based approach to identify functional modules within and across primary human immune cells.

Mola S, Foisy S, Boucher G, Major F, Beauchamp C, Karaky M PLoS One. 2020; 15(5):e0233543.

PMID: 32469933 PMC: 7259617. DOI: 10.1371/journal.pone.0233543.

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