WDR5 high expression and its effect on tumorigenesis in leukemia

被引：56

作者：

Ge, Zheng ^{[1
,2
,3
]}

Song, Evelyn J. ^{[2
]}

Kawasawa, Yuka Imamura ^{[4
]}

Li, Jianyong ^{[3
]}

Dovat, Sinisa ^{[2
]}

Song, Chunhua ^{[2
]}

机构：

[1] Southeast Univ, Sch Med, Zhongda Hosp, Dept Hematol,Key Dept Jiangsu Med, Nanjing, Jiangsu, Peoples R China

[2] Penn State Univ, Coll Med, Dept Pediat, Hershey, PA USA

[3] Nanjing Med Univ, Affiliated Hosp 1, Jiangsu Prov Hosp, Dept Hematol, Nanjing, Jiangsu, Peoples R China

[4] Penn State Coll Med, Penn State Hershey Genome Sci Facil, Hershey, PA USA

来源：

ONCOTARGET | 2016年 / 7卷 / 25期

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

WDR5; H3K4me3; MLL; leukemia; CHRONIC LYMPHOCYTIC-LEUKEMIA; MIXED-LINEAGE LEUKEMIA; ACUTE MYELOID-LEUKEMIA; H3K4 METHYLTRANSFERASE ACTIVITY; MLL FUSION PROTEINS; HISTONE H3; TYROSINE KINASE; GENE-EXPRESSION; SHARED SUBUNIT; SELF-RENEWAL;

D O I：

10.18632/oncotarget.9312

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

WD repeat domain 5 (WDR5) plays an important role in various biological functions through the epigenetic regulation of gene transcription. However, the oncogenic effect of WDR5 in leukemia remains largely unknown. Here, we found WDR5 expression is increased in leukemia patients. High expression of WDR5 is associated with high risk leukemia; Patients with WDR5 and MLL1 high expression have poor complete remission rate. We further identified the global genomic binding of WDR5 in leukemic cells and found the genomic co-localization of WDR5 binding with H3K4me3 enrichment. Moreover, WDR5 knockdown by shRNA suppresses cell proliferation, induces apoptosis, inhibits the expression of WDR5 targets, and blocks the H3K4me3 enrichment on the promoter of its targets. We also observed the positive correlation of WDR5 expression with these targets in the cohort study of leukemia patients. Our data reveal that WDR5 may have oncogenic effect and WDR5-mediated H3K4 methylation plays an important role in leukemogenesis.

引用

页码：37740 / 37754

页数：15

共 58 条

[11] In focus: MLL-rearranged leukemia [J].

de Boer, J. ;

Walf-Vorderwuelbecke, V. ;

Williams, O. .

LEUKEMIA, 2013, 27 (06) :1224-1228

[12] A critical role for Lyn in acute myeloid leukemia [J].

Dos Santos, Ceric ;

Demur, Ceile ;

Bardet, Valeie ;

Prade-Houdellier, Nais ;

Payrastre, Bernard ;

Recher, Christian .

BLOOD, 2008, 111 (04) :2269-2279

[13] Mechanisms of transcriptional regulation by MLL and its disruption in acute leukemia [J].

Dou, Yali ;

Hess, Jay L. .

INTERNATIONAL JOURNAL OF HEMATOLOGY, 2008, 87 (01) :10-18

[14] Regulation of MLL1 H3K4 methyltransferase activity by its core components [J].

Dou, Yali ;

Milne, Thomas A. ;

Ruthenburg, Alexander J. ;

Lee, Seunghee ;

Lee, Jae Woon ;

Verdine, Gregory L. ;

Allis, C. David ;

Roeder, Robert G. .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2006, 13 (08) :713-719

[15] Histone H3 lysine 4 (H3K4) methylation in development and differentiation [J].

Eissenberg, Joel C. ;

Shilatifard, Ali .

DEVELOPMENTAL BIOLOGY, 2010, 339 (02) :240-249

[16] The anti-apoptotic form of tyrosine kinase Lyn that is generated by proteolysis is degraded by the N-end rule pathway [J].

Eldeeb, Mohamed A. ;

Fahlman, Richard P. .

ONCOTARGET, 2014, 5 (09) :2714-2722

[17] Discovering Hematopoietic Mechanisms through Genome-wide Analysis of GATA Factor Chromatin Occupancy [J].

Fujiwara, Tohnu ;

O'Geen, Henriette ;

Keles, Sunduz ;

Blahnik, Kimberly ;

Linnemann, Amelia K. ;

Kang, Yoon-A. ;

Choi, Kyunghee ;

Farnham, Peggy J. ;

Bresnick, Emery H. .

MOLECULAR CELL, 2009, 36 (04) :667-681

[18] CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukaemia [J].

Gioia, Romain ;

Tregoat, Claire ;

Dumas, Pierre-Yves ;

Lagarde, Valerie ;

Prouzet-Mauleon, Valerie ;

Desplat, Vanessa ;

Sirvent, Audrey ;

Praloran, Vincent ;

Lippert, Eric ;

Villacreces, Arnaud ;

Leconet, Wilhem ;

Robert, Bruno ;

Vigon, Isabelle ;

Roche, Serge ;

Mahon, Francois-Xavier ;

Pasquet, Jean-Max .

JOURNAL OF PATHOLOGY, 2015, 237 (01) :14-24

[19]

Grebien F, 2015, NAT CHEM BIOL, V11, P571, DOI [10.1038/NCHEMBIO.1859, 10.1038/nchembio.1859]

[20] Characterization of LEF1 High Expression and Novel Mutations in Adult Acute Lymphoblastic Leukemia [J].

Guo, Xing ;

Zhang, Run ;

Liu, Juan ;

Li, Min ;

Song, Chunhua ;

Dovat, Sinisa ;

Li, Jianyong ;

Ge, Zheng .

PLOS ONE, 2015, 10 (05)

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