title: From the Cover: Neutralization of terminal differentiation in gliomagenesis.
abstract: An immature state of cellular differentiation--characterized by stem cell-like tendencies and impaired differentiation--is a hallmark of cancer. Using glioblastoma multiforme (GBM) as a model system, we sought to determine whether molecular determinants that drive cells toward terminal differentiation are also genetically targeted in carcinogenesis and whether neutralizing such genes also plays an active role to reinforce the impaired differentiation state and promote malignancy. To that end, we screened 71 genes with known roles in promoting nervous system development that also sustain copy number loss in GBM through antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNA-binding and splicing regulator that is deleted in 10% of GBM cases. Integrated in silico analysis of GBM profiles to elucidate the A2BP1 pathway and its role in glioma identified myelin transcription factor 1-like (Myt1L) as a direct transcriptional regulator of A2BP1. Reintroduction of A2BP1 or Myt1L in GBM cell lines and glioma stem cells profoundly inhibited tumorigenesis in multiple assays, and conversely, shRNA-mediated knockdown of A2BP1 or Myt1L in premalignant neural stem cells compromised neuronal lineage differentiation and promoted orthotopic tumor formation. On the mechanistic level, with the top-represented downstream target TPM1 as an illustrative example, we demonstrated that, among its multiple functions, A2BP1 serves to regulate TPM1's alternative splicing to promote cytoskeletal organization and terminal differentiation and suppress malignancy. Thus, in addition to the activation of self-renewal pathways, the neutralization of genetic programs that drive cells toward terminal differentiation may also promote immature and highly plastic developmental states that contribute to the aggressive malignant properties of GBM.
authors.affiliation: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.forename: Allen L
authors.initials: AL
authors.lastname: Ho
authors.forename: Liang
authors.initials: L
authors.lastname: Yuan
authors.forename: Baoli
authors.initials: B
authors.lastname: Hu
authors.forename: Sujun
authors.initials: S
authors.lastname: Hua
authors.forename: Soyoon Sarah
authors.initials: SS
authors.lastname: Hwang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Tianyi
authors.initials: T
authors.lastname: Hu
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zheng
authors.forename: Boyi
authors.initials: B
authors.lastname: Gan
authors.forename: Gongxiong
authors.initials: G
authors.lastname: Wu
authors.forename: Yaoqi Alan
authors.initials: YA
authors.lastname: Wang
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D005904:Glial Fibrillary Acidic Protein; C561020:MYT1L protein, human; D009419:Nerve Tissue Proteins; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D014157:Transcription Factors
keywords: cancer stem cells; oncogenomics
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Genes Dev. 2009 Oct 1;23(19):2284-93
references.pmid: 19762510
references.citation: Cell Stem Cell. 2011 Aug 5;9(2):113-8
references.pmid: 21802386
references.citation: Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7039-43
references.pmid: 8346214
references.citation: Nature. 2011 May 26;476(7359):220-3
references.pmid: 21617644
references.citation: Nature. 2004 Nov 18;432(7015):396-401
references.pmid: 15549107
references.citation: Hum Mol Genet. 2012 Oct 1;21(19):4171-86
references.pmid: 22730494
references.citation: Oncogene. 1999 Mar 18;18(11):2027-31
references.pmid: 10208425
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9618-23
references.pmid: 8790379
references.citation: Cold Spring Harb Symp Quant Biol. 2008;73:411-20
references.pmid: 19329578
references.citation: Nat Rev Clin Oncol. 2011 Feb;8(2):97-106
references.pmid: 21151206
references.citation: Nat Rev Cancer. 2009 Apr;9(4):265-73
references.pmid: 19262571
references.citation: Nature. 2010 Feb 25;463(7284):1035-41
references.pmid: 20107439
references.citation: N Engl J Med. 2005 Mar 10;352(10):987-96
references.pmid: 15758009
references.citation: Histopathology. 1997 Nov;31(5):436-43
references.pmid: 9416484
references.citation: Nature. 2011 Jul 13;476(7359):228-31
references.pmid: 21753754
references.citation: Nature. 2006 Dec 7;444(7120):756-60
references.pmid: 17051156
references.citation: Nature. 2010 Oct 28;467(7319):1109-13
references.pmid: 20981101
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Genes Dev. 2010 Aug 15;24(16):1731-45
references.pmid: 20713517
references.citation: Cancer Res. 2011 Jun 15;71(12):4055-60
references.pmid: 21628493
references.citation: Cancer Cell. 2006 May;9(5):391-403
references.pmid: 16697959
references.citation: Mol Cell Biol. 2005 Nov;25(22):10005-16
references.pmid: 16260614
references.citation: Semin Oncol. 2011 Apr;38(2):243-53
references.pmid: 21421114
references.citation: Oncogene. 2001 Apr 19;20(17):2112-21
references.pmid: 11360195
references.citation: N Engl J Med. 2012 Mar 8;366(10):883-892
references.pmid: 22397650
references.citation: Cell Stem Cell. 2009 May 8;4(5):440-52
references.pmid: 19427293
references.citation: Nature. 2008 Oct 23;455(7216):1129-33
references.pmid: 18948956
references.citation: Cell Cycle. 2009 Jan 15;8(2):284-98
references.pmid: 19177011
references.citation: J Neurooncol. 2006 May;78(1):85-90
references.pmid: 16391896
references.citation: Cancer Cell. 2007 Jan;11(1):69-82
references.pmid: 17222791
references.citation: J Biol Chem. 1998 Nov 27;273(48):32182-6
references.pmid: 9822696
references.citation: Genes Dev. 2007 Nov 1;21(21):2683-710
references.pmid: 17974913
references.citation: EMBO J. 2003 Feb 17;22(4):905-12
references.pmid: 12574126
references.citation: Mol Cancer. 2010 Jul 20;9:194
references.pmid: 20646316
references.citation: Nature. 2010 Feb 18;463(7283):899-905
references.pmid: 20164920
references.citation: Biochem Biophys Res Commun. 1988 Dec 30;157(3):1111-6
references.pmid: 3061377
references.citation: Nat Protoc. 2006;1(1):302-7
references.pmid: 17406249
references.citation: Mol Cancer Res. 2012 Mar;10(3):293-304
references.pmid: 22267545
references.citation: Somat Cell Mol Genet. 1998 Sep;24(5):273-80
references.pmid: 10696235
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10343-8
references.pmid: 21646515
references.citation: Nature. 2011 Apr 7;472(7341):90-4
references.pmid: 21399628
references.citation: Adv Exp Med Biol. 2008;644:124-31
references.pmid: 19209818
references.citation: Nat Genet. 2011 May 29;43(7):706-11
references.pmid: 21623373
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15178-83
references.pmid: 14645703
references.citation: Cell. 2012 Feb 17;148(4):651-63
references.pmid: 22341440
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11501-6
references.pmid: 20534551
references.citation: Cancer Cell. 2010 May 18;17(5):497-509
references.pmid: 20478531
references.citation: Nature. 2008 Oct 23;455(7216):1061-8
references.pmid: 18772890
references.citation: Neuro Oncol. 2004 Jul;6(3):253-8
references.pmid: 15279718