The PAF Complex Synergizes with MLL Fusion Proteins at HOX Loci to Promote Leukemogenesis

被引：184

作者：

Muntean, Andrew G. ^{[1
]}

Tan, Jiaying ^{[1
]}

Sitwala, Kajal ^{[1
]}

Huang, Yongsheng ^{[2
]}

Bronstein, Joel ^{[1
]}

Connelly, James A. ^{[1
]}

Basrur, Venkatesha ^{[1
]}

Elenitoba-Johnson, Kojo S. J. ^{[1
]}

Hess, Jay L. ^{[1
]}

机构：

[1] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Sch Med, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

来源：

CANCER CELL | 2010年 / 17卷 / 06期

基金：

美国国家卫生研究院;

关键词：

RNA-POLYMERASE-II; TUMOR-SUPPRESSOR PROTEIN; HISTONE H2B; TRANSCRIPTIONAL ELONGATION; H3; METHYLATION; CHROMOSOMAL TRANSLOCATIONS; TARGET GENES; STEM-CELLS; EXPRESSION; LEUKEMIA;

D O I：

10.1016/j.ccr.2010.04.012

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

MLL is involved in chromosomal rearrangements that generate fusion proteins with deregulated transcriptional activity. The mechanisms of MLL fusion protein-mediated transcriptional activation are poorly understood. Here we show MLL interacts directly with the polymerase associated factor complex (PAFc) through sequences flanking the CxxC domain. PAFc interacts with RNA polymerase II and stimulates posttranslational histone modifications. PAFc augments MLL and MLL-AF9 mediated transcriptional activation of Hoxa9. Conversely, knockdown of PAFc disrupts MLL fusion protein-mediated transcriptional activation and MLL recruitment to target loci. PAFc gene expression is downregulated during hematopoiesis and likely serves to regulate MLL function. Deletions of MLL that abolish interactions with PAFc also eliminate MLL-AF9 mediated immortalization indicating an essential function for this interaction in leukemogenesis.

引用

页码：609 / 621

页数：13

共 54 条

[1] Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase [J].

Allen, Mark D. ;

Grummitt, Charles G. ;

Hilcenko, Christine ;

Min, Sandra Young ;

Tonkin, Louise M. ;

Johnson, Christopher M. ;

Freund, Stefan M. ;

Bycroft, Mark ;

Warren, Alan J. .

EMBO JOURNAL, 2006, 25 (19) :4503-4512

[2] Chromosomal translocations involving the MLL gene:: Molecular mechanisms [J].

Aplan, Peter D. .

DNA REPAIR, 2006, 5 (9-10) :1265-1272

[3] MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia [J].

Armstrong, SA ;

Staunton, JE ;

Silverman, LB ;

Pieters, R ;

de Boer, ML ;

Minden, MD ;

Sallan, SE ;

Lander, ES ;

Golub, TR ;

Korsmeyer, SJ .

NATURE GENETICS, 2002, 30 (01) :41-47

[4] Binding to nonmethylated CpG DNA is essential for target recognition, transactivation, and myeloid transformation by an MLL oncoprotein [J].

Ayton, PM ;

Chen, EH ;

Cleary, ML .

MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (23) :10470-10478

[5] Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9 [J].

Ayton, PM ;

Cleary, ML .

GENES & DEVELOPMENT, 2003, 17 (18) :2298-2307

[6] Alterations of the CxxC domain preclude oncogenic activation of mixed-lineage leukemia 2 [J].

Bach, C. ;

Mueller, D. ;

Buhl, S. ;

Garcia-Cuellar, M. P. ;

Slany, R. K. .

ONCOGENE, 2009, 28 (06) :815-823

[7]

BATRA SK, 1991, CELL GROWTH DIFFER, V2, P385

[8] An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors [J].

Ben-Porath, Ittai ;

Thomson, Matthew W. ;

Carey, Vincent J. ;

Ge, Ruping ;

Bell, George W. ;

Regev, Aviv ;

Weinberg, Robert A. .

NATURE GENETICS, 2008, 40 (05) :499-507

[9] Interaction of MLL amino terminal sequences with menin is required for transformation [J].

Caslini, Corrado ;

Yang, Zhaohai ;

El-Osta, Mohamad ;

Milne, Thomas A. ;

Slany, Robeft K. ;

Hess, Jay L. .

CANCER RESEARCH, 2007, 67 (15) :7275-7283

[10] Positional cloning of the gene for multiple endocrine neoplasia-type 1 [J].

Chandrasekharappa, SC ;

Guru, SC ;

Manickam, P ;

Olufemi, SE ;

Collins, FS ;

EmmertBuck, MR ;

Debelenko, LV ;

Zhuang, ZP ;

Lubensky, IA ;

Liotta, LA ;

Crabtree, JS ;

Wang, YP ;

Roe, BA ;

Weisemann, J ;

Boguski, MS ;

Agarwal, SK ;

Kester, MB ;

Kim, YS ;

Heppner, C ;

Dong, QH ;

Spiegel, AM ;

Burns, AL ;

Marx, SJ .

SCIENCE, 1997, 276 (5311) :404-407

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