A tumorigenic MLL-homeobox network in human glioblastoma stem cells.

Glioblastoma growth is driven by cancer cells that have stem cell properties, but molecular determinants of their tumorigenic behavior are poorly defined. In cancer, altered activity of the epigenetic modifiers Polycomb and Trithorax complexes may contribute to the neoplastic phenotype. Here, we provide the first mechanistic insights into the role of the Trithorax protein mixed lineage leukemia (MLL) in maintaining cancer stem cell characteristics in human glioblastoma. We found that MLL directly activates the Homeobox gene HOXA10. In turn, HOXA10 activates a downstream Homeobox network and other genes previously characterized for their role in tumorigenesis. The MLL-Homeobox axis we identified significantly contributes to the tumorigenic potential of glioblastoma stem cells. Our studies suggest a role for MLL in contributing to the epigenetic heterogeneity between tumor-initiating and non-tumor-initiating cells in glioblastoma.

[1]  Giacomo Cavalli,et al.  Trithorax group proteins: switching genes on and keeping them active , 2011, Nature Reviews Molecular Cell Biology.

[2]  Manuel Hidalgo,et al.  Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. , 2011, Cell stem cell.

[3]  Angelo J. Canty,et al.  Stem cell gene expression programs influence clinical outcome in human leukemia , 2011, Nature Medicine.

[4]  A. Sloan,et al.  Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential , 2011, Cell Death and Differentiation.

[5]  Lars Bullinger,et al.  MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. , 2011, Cancer cell.

[6]  Yi Zhang,et al.  DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. , 2011, Blood.

[7]  Amanda J. Wilson,et al.  Functional crosstalk between Bmi1 and MLL/Hoxa9 axis in establishment of normal hematopoietic and leukemic stem cells. , 2011, Cell stem cell.

[8]  E. Eklund,et al.  HoxA10 Activates CDX4 Transcription and Cdx4 Activates HOXA10 Transcription in Myeloid Cells* , 2011, The Journal of Biological Chemistry.

[9]  Zev A. Binder,et al.  The Genetic Landscape of the Childhood Cancer Medulloblastoma , 2011, Science.

[10]  R. Reis,et al.  MGMT-independent temozolomide resistance in pediatric glioblastoma cells associated with a PI3-kinase-mediated HOX/stem cell gene signature. , 2010, Cancer research.

[11]  T. Brümmendorf,et al.  Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase subunit TERT , 2010, Leukemia.

[12]  R. Wilson,et al.  Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. , 2010, Cancer cell.

[13]  R. McLendon,et al.  Integrin alpha 6 regulates glioblastoma stem cells. , 2010, Cell stem cell.

[14]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[15]  Jane Fridlyand,et al.  Reversing HOXA9 oncogene activation by PI3K inhibition: epigenetic mechanism and prognostic significance in human glioblastoma. , 2010, Cancer research.

[16]  G. Bernier,et al.  BMI1 Sustains Human Glioblastoma Multiforme Stem Cell Renewal , 2009, The Journal of Neuroscience.

[17]  Mark Bernstein,et al.  Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. , 2009, Cell stem cell.

[18]  J. Costello,et al.  Epigenetic mechanisms in glioblastoma multiforme. , 2009, Seminars in cancer biology.

[19]  H. Fine,et al.  SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. , 2009, Cell stem cell.

[20]  J. García-Verdugo,et al.  Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells , 2009, Nature.

[21]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[22]  J. Herman,et al.  Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. , 2008, Cancer research.

[23]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[24]  E. Domany,et al.  Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  G. Parkin,et al.  Long-term tripotent differentiation capacity of human neural stem (NS) cells in adherent culture , 2008, Molecular and Cellular Neuroscience.

[26]  Yuri Kotliarov,et al.  Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. , 2008, Cancer cell.

[27]  Scott A. Armstrong,et al.  MLL translocations, histone modifications and leukaemia stem-cell development , 2007, Nature Reviews Cancer.

[28]  O. van Tellingen,et al.  Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. , 2007, Cancer cell.

[29]  R. Humphries,et al.  Hox genes in hematopoiesis and leukemogenesis , 2007, Oncogene.

[30]  R. Humphries,et al.  Candidate Genes for Expansion and Transformation of Hematopoietic Stem Cells by NUP98-HOX Fusion Genes , 1997, Environmental health perspectives.

[31]  J. McPherson,et al.  Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets. , 2006, Carcinogenesis.

[32]  P. Laird,et al.  CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer , 2006, Nature Genetics.

[33]  Felix Naef,et al.  In vivo transcriptional profile analysis reveals RNA splicing and chromatin remodeling as prominent processes for adult neurogenesis , 2006, Molecular and Cellular Neuroscience.

[34]  D. Grier,et al.  Continuous MLL-ENL expression is necessary to establish a "Hox Code" and maintain immortalization of hematopoietic progenitor cells. , 2005, Cancer research.

[35]  Austin G Smith,et al.  Niche-Independent Symmetrical Self-Renewal of a Mammalian Tissue Stem Cell , 2005, PLoS biology.

[36]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[37]  L. Zon,et al.  An Mll-Dependent Hox Program Drives Hematopoietic Progenitor Expansion , 2004, Current Biology.

[38]  R. Henkelman,et al.  Identification of human brain tumour initiating cells , 2004, Nature.

[39]  Ugo Orfanelli,et al.  Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma , 2004, Cancer Research.

[40]  A. Feinberg,et al.  The history of cancer epigenetics , 2004, Nature Reviews Cancer.

[41]  Cynthia Hawkins,et al.  Identification of a cancer stem cell in human brain tumors. , 2003, Cancer research.

[42]  M. Cleary,et al.  Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. , 2003, Genes & development.

[43]  S. Armstrong,et al.  Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation. , 2003, Blood.

[44]  Thomas A Milne,et al.  MLL targets SET domain methyltransferase activity to Hox gene promoters. , 2002, Molecular cell.

[45]  P. Fernandez,et al.  Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation. , 2001, Genes & development.

[46]  R. Humphries,et al.  Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells , 1999, Leukemia.

[47]  T. Komori,et al.  Growth disturbance in fetal liver hematopoiesis of Mll-mutant mice. , 1998, Blood.

[48]  S. Korsmeyer,et al.  Defects in yolk sac hematopoiesis in Mll-null embryos. , 1997, Blood.

[49]  S. Baylin,et al.  DNA hypermethylation is associated with 17p allelic loss in neural tumors. , 1993, Cancer research.

[50]  S. Weiss,et al.  Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. , 1992, Science.

[51]  R. Krumlauf,et al.  Segmental expression of Hox-2 homoeobox-containing genes in the developing mouse hindbrain , 1989, Nature.

[52]  Peter A. Jones,et al.  Epigenetics in cancer. , 2010, Carcinogenesis.

[53]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[54]  E. Lander,et al.  MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia , 2002, Nature Genetics.

[55]  P. Bunn,et al.  Altered HOX and WNT7A expression in human lung cancer. , 2000, Proceedings of the National Academy of Sciences of the United States of America.