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Transcriptional circuits in B cell transformation
Yeguang Hu1, Toshimi Yoshida, Katia Georgopoulos
1Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Current Opinion in Hematology
|May 3, 2017
Summary
Loss of IKAROS in B cell precursors blocks differentiation and promotes leukemia. Understanding IKAROS transcriptional circuits offers new ways to classify and treat high-risk B-cell acute lymphoblastic leukemia (B-ALL).
Area of Science:
- Molecular Biology
- Cell Biology
- Hematology
Background:
- IKAROS is crucial for normal B cell differentiation.
- Loss of IKAROS function leads to aberrant cellular properties and a high-risk phenotype in B cell acute lymphoblastic leukemia (B-ALL).
Purpose of the Study:
- To elucidate the role of IKAROS in regulating transcriptional circuits during B cell development.
- To understand how IKAROS deregulation contributes to the pathogenesis of high-risk B-ALL.
Main Methods:
- Analysis of IKAROS's role in super-enhancer activity and gene regulation.
- Investigation of IKAROS's interaction with master B cell regulators (EBF1, PAX5) and the Polycomb repression complex (PRC2).
- Examination of IKAROS's repression of 'extra-lineage' transcription factors.
Main Results:
- IKAROS is essential for pre-B cell receptor (BCR) signaling and differentiation by controlling super-enhancer activity.
- IKAROS represses a network of transcription factors (YAP1, TEAD1/2, LHX2, LMO2) normally absent in lymphocytes.
- Deregulation of IKAROS leads to de-novo enhancer formation, loss of repression, and acquisition of aberrant, epithelial-like cell properties.
Conclusions:
- IKAROS-based transcriptional circuits provide new insights into cell differentiation.
- Understanding these circuits offers novel approaches for classifying and treating early-stage, high-risk human B-ALL.
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