Home LiteratureArticle Details
PMID: 20159607 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele.

Cancer cell ·Vol. 17 ·No. 2 ·2010-02-17 ·Pages 148-59

Thiel AT, Blessington P, Zou T, Feather D, Wu X, Yan J, Zhang H, Liu Z, Ernst P, Koretzky GA, Hua X

Abstract

Oncogenic fusion proteins are capable of initiating tumorigenesis, but the role of their wild-type counterparts in this process is poorly understood. The mixed lineage leukemia (MLL) gene undergoes chromosomal translocations, resulting in the formation of oncogenic MLL fusion proteins (MLL-FPs). Here, we show that menin recruits both wild-type MLL and oncogenic MLL-AF9 fusion protein to the loci of HOX genes to activate their transcription. Wild-type MLL not only catalyzes histone methylation at key target genes but also controls distinct MLL-AF9-induced histone methylation. Notably, the wild-type Mll allele is required for MLL-AF9-induced leukemogenesis and maintenance of MLL-AF9-transformed cells. These findings suggest an essential cooperation between an oncogene and its wild-type counterpart in MLL-AF9-induced leukemogenesis.

MeSH Terms
Alleles Animals Gene Expression Regulation, Leukemic Histones/metabolism Homeodomain Proteins/genetics,metabolism Humans Leukemia/genetics Methylation Mice Myeloid-Lymphoid Leukemia Protein/chemistry,genetics,physiology Oncogene Proteins, Fusion/chemistry,genetics,physiology Proto-Oncogene Proteins/metabolism Translocation, Genetic
Chemicals
Histones Homeodomain Proteins MEN1 protein, human Oncogene Proteins, Fusion Proto-Oncogene Proteins Myeloid-Lymphoid Leukemia Protein
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Thiel Austin T
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, 19104, USA.
Blessington Peter
Zou Tao
Feather Danielle
Wu Xinjiang
Yan Jizhou
Zhang Hui
Liu Zuguo
Ernst Patricia
Koretzky Gary A
Hua Xianxin
References (49)
49 references, click to expand
  1. Global and Hox-specific roles for the MLL1 methyltransferase.
    Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8603-8 PMID: 15941828
  2. MLL: how complex does it get?
    J Cell Biochem. 2005 May 15;95(2):234-42 PMID: 15779005
  3. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation.
    Mol Cell. 2002 Nov;10(5):1119-28 PMID: 12453419
  4. Cdx4 and menin co-regulate Hoxa9 expression in hematopoietic cells.
    PLoS One. 2006 Dec 20;1:e47 PMID: 17183676
  5. Modeling the initiation and progression of human acute leukemia in mice.
    Science. 2007 Apr 27;316(5824):600-4 PMID: 17463288
  6. Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss.
    Cell Stem Cell. 2007 Jun 7;1(1):113-26 PMID: 18371340
  7. Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications.
    Cancer Res. 2005 Dec 15;65(24):11367-74 PMID: 16357144
  8. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.
    Nat Genet. 2002 Jan;30(1):41-7 PMID: 11731795
  9. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis.
    Cell. 2005 Oct 21;123(2):207-18 PMID: 16239140
  10. The complex language of chromatin regulation during transcription.
    Nature. 2007 May 24;447(7143):407-12 PMID: 17522673
  11. Non-oncogene addiction and the stress phenotype of cancer cells.
    Cell. 2007 Sep 21;130(6):986-8 PMID: 17889643
  12. The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy.
    Blood. 2005 Jul 1;106(1):345-52 PMID: 15774615
  13. hDOT1L links histone methylation to leukemogenesis.
    Cell. 2005 Apr 22;121(2):167-78 PMID: 15851025
  14. MLL translocations, histone modifications and leukaemia stem-cell development.
    Nat Rev Cancer. 2007 Nov;7(11):823-33 PMID: 17957188
  15. Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia.
    Genes Dev. 2008 Dec 15;22(24):3403-8 PMID: 19141473
  16. Double chromodomains cooperate to recognize the methylated histone H3 tail.
    Nature. 2005 Dec 22;438(7071):1181-5 PMID: 16372014
  17. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification.
    Blood. 2007 Dec 15;110(13):4445-54 PMID: 17855633
  18. Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9.
    Genes Dev. 2003 Sep 15;17(18):2298-307 PMID: 12952893
  19. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b.
    EMBO J. 1998 Jul 1;17(13):3714-25 PMID: 9649441
  20. Menin critically links MLL proteins with LEDGF on cancer-associated target genes.
    Cancer Cell. 2008 Jul 8;14(1):36-46 PMID: 18598942
  21. Chromosomal translocations in cancer.
    Biochim Biophys Acta. 2008 Dec;1786(2):139-52 PMID: 18718509
  22. Proteolysis of MLL family proteins is essential for taspase1-orchestrated cell cycle progression.
    Genes Dev. 2006 Sep 1;20(17):2397-409 PMID: 16951254
  23. MLL: a histone methyltransferase disrupted in leukemia.
    Trends Mol Med. 2004 Oct;10(10):500-7 PMID: 15464450
  24. Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells.
    Cancer Cell. 2008 May;13(5):432-40 PMID: 18455126
  25. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus.
    Mol Cell. 2004 Feb 27;13(4):587-97 PMID: 14992727
  26. Menin associates with FANCD2, a protein involved in repair of DNA damage.
    Cancer Res. 2003 Jul 15;63(14):4204-10 PMID: 12874027
  27. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling.
    Hum Mol Genet. 2007 Jan 1;16(1):92-106 PMID: 17135274
  28. Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions.
    Genes Dev. 2007 Oct 1;21(19):2385-98 PMID: 17908926
  29. MLL targets SET domain methyltransferase activity to Hox gene promoters.
    Mol Cell. 2002 Nov;10(5):1107-17 PMID: 12453418
  30. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia.
    Cancer Cell. 2006 Oct;10(4):257-68 PMID: 17045204
  31. The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin.
    Oncogene. 2005 Aug 18;24(35):5525-32 PMID: 15856011
  32. The Mll partial tandem duplication: differential, tissue-specific activity in the presence or absence of the wild-type allele.
    Blood. 2008 Sep 15;112(6):2508-11 PMID: 18617636
  33. Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors.
    Cell Stem Cell. 2007 Sep 13;1(3):324-37 PMID: 18371366
  34. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia.
    Cancer Cell. 2008 Jun;13(6):483-95 PMID: 18538732
  35. Interaction of MLL amino terminal sequences with menin is required for transformation.
    Cancer Res. 2007 Aug 1;67(15):7275-83 PMID: 17671196
  36. Direct binding of DNA by tumor suppressor menin.
    J Biol Chem. 2004 Nov 19;279(47):49045-54 PMID: 15331604
  37. Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization.
    Mol Cell Biol. 2003 Jan;23(1):186-94 PMID: 12482972
  38. The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression.
    Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):1018-23 PMID: 16415155
  39. H3K79 methylation profiles define murine and human MLL-AF4 leukemias.
    Cancer Cell. 2008 Nov 4;14(5):355-68 PMID: 18977325
  40. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development.
    Cell. 2005 Jun 17;121(6):859-72 PMID: 15960974
  41. Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCalpha in an aldosterone-sensitive manner.
    J Biol Chem. 2006 Jun 30;281(26):18059-68 PMID: 16636056
  42. Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL.
    EMBO J. 1997 Jul 16;16(14):4226-37 PMID: 9250666
  43. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9.
    Nature. 2006 Aug 17;442(7104):818-22 PMID: 16862118
  44. Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal.
    Cell Stem Cell. 2007 Sep 13;1(3):338-45 PMID: 18371367
  45. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF.
    Nature. 2006 Jul 6;442(7098):91-5 PMID: 16728978
  46. Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells.
    Cancer Res. 2006 Jun 1;66(11):5707-15 PMID: 16740708
  47. DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells.
    Mol Cell Biol. 2008 Apr;28(8):2825-39 PMID: 18285465
  48. Myc-binding-site recognition in the human genome is determined by chromatin context.
    Nat Cell Biol. 2006 Jul;8(7):764-70 PMID: 16767079
  49. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling.
    Nature. 2006 Jul 6;442(7098):86-90 PMID: 16728976
Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2009.12.034
Published
2010-02-17
Pages
148-59
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2830208
Subset
IM
Grants
NCI NIH HHS · R01 CA113962 · United States
NCI NIH HHS · R01 CA113962-05 · United States
NCI NIH HHS · T32 CA009140 · United States
NCI NIH HHS · R01 CA100912 · United States
NCI NIH HHS · T32 CA09140 · United States
NCI NIH HHS · R01 CA100912-05 · United States
External Links
PubMed source DOI: 10.1016/j.ccr.2009.12.034 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2