File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
  • Find via Find It@HKUL
Supplementary

Conference Paper: Altered Enhancer Activity Represses CEBPE Expression in MLL -Rearranged Leukemia

TitleAltered Enhancer Activity Represses CEBPE Expression in MLL -Rearranged Leukemia
Authors
Issue Date2017
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
59th American Society of Hematology (ASH) Annual Meeting and Exposition, Atlanta, USA, 9-12 December 2017. In Blood, 2017, v. 130 n. Suppl. 1, p. 1207 How to Cite?
AbstractMixed lineage leukemia (MLL)-rearranged leukemia is characterized by the presence of MLL fusion proteins resulting from chromosomal translocation between MLL and its partner genes. The resultant fusion proteins can confer aberrant epigenetic patterns at gene regulatory elements to disrupt transcriptional program, and ultimately leads to differentiation blockage at early hematopoietic progenitor stage. CCAAT enhancer binding proteins (C/EBPs) are key transcription factors involved in myeloid lineage commitment and maturation, among which CEBPE is crucial in terminal differentiation of granulocytes/macrophages. We found that Cebpe is markedly downregulated in murine hematopoietic stem/progenitor cells (HSPCs) expressing MLL-EEN, which could be associated with differentiation blockage in MLL -rearranged leukemia. However, how CEBPE is epigenetically dysregulated by MLL fusion proteins remains unclear. In murine granulocytes, we demonstrated long-range chromatin interaction between Cebpe promoter and enhancer by chromatin conformation capture (3C) assay, conferring the strong expression of Cebpe . Strikingly, we noticed gain of DNA methylation at Cebpe promoter in MLL-EEN expressing HSPCs, suggesting the disruption of chromatin interaction through aberrant epigenetic alterations resulted in Cebpe repression. Interestingly, CEBPE expression was also found significantly lower in human MLL acute myeloid leukemia (AML) cell lines (HL60, NB4, U937 and Kasumi-1), when compared to non-MLL AML cell lines (ML-2, MV4:11, Monomac-6 and THP-1). DNA hypermethylation was observed at both promoter and predicated enhancer regions in MLL AML cells, which were absent in non-MLL AML cells. In addition, reduction of H3K27ac enrichment at the predicted enhancer was found in MLL AML cells. Analysis of the public available RNA Polymerase II (RNAPII) ChIP-seq data demonstrated RNAPII binding at both CEBPE promoter and enhancers in non-MLL AML cell lines, but it was absent at the enhancer region in MLL AML cells. These results suggest a common epigenetic mechanism which disrupts the CEBPE enhancer-promoter interaction in MLL -rearranged leukemia. Besides, treatment of MLL AML cell lines with DNA methylation inhibitor 5'-aza-cytidine (5-aza-C) demonstrated induction of CEBPE and myeloid marker CD11b . While all -trans retinoid acid failed to trigger cell differentiation in ML-2 AML cells, co-treatment with 5-aza-C resulted in further induction of CEBPE and CD11b, compared to 5-aza-C treatment per se . Collectively, our work shows that aberrant DNA methylation mediated by MLL fusion proteins represses CEBPE expression through altering its enhancer activity, which subsequently leads to cell differentiation blockage in MLL AML cells. This study provides novel insights on the aberrant epigenetic regulation in MLL -rearranged leukemia and facilitates the development of differentiation therapy for leukemia.
Persistent Identifierhttp://hdl.handle.net/10722/261278
ISSN
2017 Impact Factor: 15.132
2015 SCImago Journal Rankings: 6.395

 

DC FieldValueLanguage
dc.contributor.authorYang, X-
dc.contributor.authorLam, YM-
dc.contributor.authorLui, WC-
dc.contributor.authorNg, RK-
dc.date.accessioned2018-09-14T08:55:36Z-
dc.date.available2018-09-14T08:55:36Z-
dc.date.issued2017-
dc.identifier.citation59th American Society of Hematology (ASH) Annual Meeting and Exposition, Atlanta, USA, 9-12 December 2017. In Blood, 2017, v. 130 n. Suppl. 1, p. 1207-
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/261278-
dc.description.abstractMixed lineage leukemia (MLL)-rearranged leukemia is characterized by the presence of MLL fusion proteins resulting from chromosomal translocation between MLL and its partner genes. The resultant fusion proteins can confer aberrant epigenetic patterns at gene regulatory elements to disrupt transcriptional program, and ultimately leads to differentiation blockage at early hematopoietic progenitor stage. CCAAT enhancer binding proteins (C/EBPs) are key transcription factors involved in myeloid lineage commitment and maturation, among which CEBPE is crucial in terminal differentiation of granulocytes/macrophages. We found that Cebpe is markedly downregulated in murine hematopoietic stem/progenitor cells (HSPCs) expressing MLL-EEN, which could be associated with differentiation blockage in MLL -rearranged leukemia. However, how CEBPE is epigenetically dysregulated by MLL fusion proteins remains unclear. In murine granulocytes, we demonstrated long-range chromatin interaction between Cebpe promoter and enhancer by chromatin conformation capture (3C) assay, conferring the strong expression of Cebpe . Strikingly, we noticed gain of DNA methylation at Cebpe promoter in MLL-EEN expressing HSPCs, suggesting the disruption of chromatin interaction through aberrant epigenetic alterations resulted in Cebpe repression. Interestingly, CEBPE expression was also found significantly lower in human MLL acute myeloid leukemia (AML) cell lines (HL60, NB4, U937 and Kasumi-1), when compared to non-MLL AML cell lines (ML-2, MV4:11, Monomac-6 and THP-1). DNA hypermethylation was observed at both promoter and predicated enhancer regions in MLL AML cells, which were absent in non-MLL AML cells. In addition, reduction of H3K27ac enrichment at the predicted enhancer was found in MLL AML cells. Analysis of the public available RNA Polymerase II (RNAPII) ChIP-seq data demonstrated RNAPII binding at both CEBPE promoter and enhancers in non-MLL AML cell lines, but it was absent at the enhancer region in MLL AML cells. These results suggest a common epigenetic mechanism which disrupts the CEBPE enhancer-promoter interaction in MLL -rearranged leukemia. Besides, treatment of MLL AML cell lines with DNA methylation inhibitor 5'-aza-cytidine (5-aza-C) demonstrated induction of CEBPE and myeloid marker CD11b . While all -trans retinoid acid failed to trigger cell differentiation in ML-2 AML cells, co-treatment with 5-aza-C resulted in further induction of CEBPE and CD11b, compared to 5-aza-C treatment per se . Collectively, our work shows that aberrant DNA methylation mediated by MLL fusion proteins represses CEBPE expression through altering its enhancer activity, which subsequently leads to cell differentiation blockage in MLL AML cells. This study provides novel insights on the aberrant epigenetic regulation in MLL -rearranged leukemia and facilitates the development of differentiation therapy for leukemia.-
dc.languageeng-
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/-
dc.relation.ispartofBlood-
dc.relation.ispartof59th American Society of Hematology (ASH) Annual Meeting and Exposition, Atlanta, USA-
dc.titleAltered Enhancer Activity Represses CEBPE Expression in MLL -Rearranged Leukemia-
dc.typeConference_Paper-
dc.identifier.emailLam, YM: simonyuk@hku.hk-
dc.identifier.emailLui, WC: afssv1@HKUCC-COM.hku.hk-
dc.identifier.emailNg, RK: raykitng@hku.hk-
dc.identifier.authorityNg, RK=rp00273-
dc.identifier.hkuros291292-
dc.identifier.volume130-
dc.identifier.issueSuppl. 1-
dc.identifier.spage1207-
dc.identifier.epage1207-
dc.publisher.placeUnited States-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats