Home LiteratureArticle Details
PMID: 18371366 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors.

Cell stem cell ·Vol. 1 ·No. 3 ·2007-09-13 ·Pages 324-37

Jude CD, Climer L, Xu D, Artinger E, Fisher JK, Ernst P

Abstract

The Mixed Lineage Leukemia (MLL) gene is essential for embryonic hematopoietic stem cell (HSC) development, but its role during adult hematopoiesis is unknown. Using an inducible knockout model, we demonstrate that Mll is essential for the maintenance of adult HSCs and progenitors, with fatal bone marrow failure occurring within 3 weeks of Mll deletion. Mll-deficient cells are selectively lost from mixed bone marrow chimeras, demonstrating their failure to self-renew even in an intact bone marrow environment. Surprisingly, HSCs lacking Mll exhibit ectopic cell-cycle entry, resulting in the depletion of quiescent HSCs. In contrast, Mll deletion in myelo-erythroid progenitors results in reduced proliferation and reduced response to cytokine-induced cell-cycle entry. Committed lymphoid and myeloid cells no longer require Mll, defining the early multipotent stages of hematopoiesis as Mll dependent. These studies demonstrate that Mll plays selective and independent roles within the hematopoietic system, maintaining quiescence in HSCs and promoting proliferation in progenitors.

MeSH Terms
Alleles Animals Bone Marrow/pathology Cell Count Cell Death Cell Differentiation Cell Line Cell Lineage Cell Proliferation Cell Survival Chimera Erythroid Precursor Cells/cytology Exons/genetics Hematopoietic Stem Cells/cytology,metabolism Homeostasis Humans Mice Myeloid Cells/cytology Myeloid Progenitor Cells/cytology Myeloid-Lymphoid Leukemia Protein/metabolism Sequence Deletion Sequence Homology, Amino Acid
Chemicals
Myeloid-Lymphoid Leukemia Protein
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Jude Craig D
Department of Genetics and Norris Cotton Cancer Center, Dartmouth Medical School, 725 Remsen, HB7400, Hanover, NH 03755, USA.
Climer Leslie
Xu Diyong
Artinger Erika
Fisher Jill K
Ernst Patricia
References (52)
52 references, click to expand
  1. Definitive hematopoiesis requires the mixed-lineage leukemia gene.
    Dev Cell. 2004 Mar;6(3):437-43 PMID: 15030765
  2. A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias.
    Nat Genet. 1993 Aug;4(4):431 PMID: 8401594
  3. MLL3, a new human member of the TRX/MLL gene family, maps to 7q36, a chromosome region frequently deleted in myeloid leukaemia.
    Gene. 2002 Feb 6;284(1-2):73-81 PMID: 11891048
  4. The MLL fusion gene, MLL-AF4, regulates cyclin-dependent kinase inhibitor CDKN1B (p27kip1) expression.
    Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14028-33 PMID: 16169901
  5. Loss of expression of the Hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells.
    Blood. 2005 Dec 1;106(12):3988-94 PMID: 16091451
  6. Inducible gene targeting in mice.
    Science. 1995 Sep 8;269(5229):1427-9 PMID: 7660125
  7. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
    Methods. 2001 Dec;25(4):402-8 PMID: 11846609
  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. An Mll-dependent Hox program drives hematopoietic progenitor expansion.
    Curr Biol. 2004 Nov 23;14(22):2063-9 PMID: 15556871
  11. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells.
    Science. 2005 Feb 18;307(5712):1101-4 PMID: 15718471
  12. Analysis of HSC activity and compensatory Hox gene expression profile in Hoxb cluster mutant fetal liver cells.
    Blood. 2006 Jul 1;108(1):116-22 PMID: 16339407
  13. Growth disturbance in fetal liver hematopoiesis of Mll-mutant mice.
    Blood. 1998 Jul 1;92(1):108-17 PMID: 9639506
  14. Biological and therapeutic aspects of infant leukemia.
    Blood. 2000 Jul 1;96(1):24-33 PMID: 10891426
  15. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins.
    Oncogene. 2001 Sep 10;20(40):5695-707 PMID: 11607819
  16. Altered Hox expression and segmental identity in Mll-mutant mice.
    Nature. 1995 Nov 30;378(6556):505-8 PMID: 7477409
  17. Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9.
    Genes Dev. 2003 Sep 15;17(18):2298-307 PMID: 12952893
  18. Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties.
    Blood. 2002 Nov 15;100(10):3710-8 PMID: 12393701
  19. 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
  20. Truncation of the Mll gene in exon 5 by gene targeting leads to early preimplantation lethality of homozygous embryos.
    Genesis. 2001 Aug;30(4):201-12 PMID: 11536426
  21. The versatile mixed lineage leukaemia gene MLL and its many associations in leukaemogenesis.
    Semin Cancer Biol. 2005 Jun;15(3):175-88 PMID: 15826832
  22. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias.
    Cell. 1992 Nov 13;71(4):691-700 PMID: 1423624
  23. Epigenetic inheritance of active chromatin after removal of the main transactivator.
    Science. 1999 Oct 29;286(5441):955-8 PMID: 10542150
  24. 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
  25. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells.
    Cell. 2005 Jul 1;121(7):1109-21 PMID: 15989959
  26. Hoxb4-deficient mice undergo normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cells.
    Blood. 2004 Jun 1;103(11):4126-33 PMID: 14962901
  27. Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll.
    Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6629-34 PMID: 16618927
  28. Regulation of MLL1 H3K4 methyltransferase activity by its core components.
    Nat Struct Mol Biol. 2006 Aug;13(8):713-9 PMID: 16878130
  29. Continuous MLL-ENL expression is necessary to establish a "Hox Code" and maintain immortalization of hematopoietic progenitor cells.
    Cancer Res. 2005 Oct 15;65(20):9245-52 PMID: 16230385
  30. 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
  31. Identification of clonogenic common lymphoid progenitors in mouse bone marrow.
    Cell. 1997 Nov 28;91(5):661-72 PMID: 9393859
  32. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression.
    Mol Cell Biol. 2004 Jul;24(13):5639-49 PMID: 15199122
  33. MLL targets SET domain methyltransferase activity to Hox gene promoters.
    Mol Cell. 2002 Nov;10(5):1107-17 PMID: 12453418
  34. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia.
    Cancer Cell. 2006 Oct;10(4):257-68 PMID: 17045204
  35. Topoisomerase II inhibitor-related acute myeloid leukaemia.
    Br J Haematol. 2000 Apr;109(1):13-23 PMID: 10848777
  36. Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes.
    Nat Struct Mol Biol. 2006 Sep;13(9):852-4 PMID: 16892064
  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. Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia.
    Blood. 2004 Mar 1;103(5):1823-8 PMID: 14615372
  39. Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product.
    Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7884-8 PMID: 7689231
  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. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene.
    Cell. 1992 Nov 13;71(4):701-8 PMID: 1423625
  42. The Drosophila Fab-7 chromosomal element conveys epigenetic inheritance during mitosis and meiosis.
    Cell. 1998 May 15;93(4):505-18 PMID: 9604927
  43. Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax.
    Oncogene. 1997 Jul 31;15(5):549-60 PMID: 9247308
  44. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9.
    Nature. 2006 Aug 17;442(7104):818-22 PMID: 16862118
  45. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors.
    Genes Dev. 2003 Dec 15;17(24):3029-35 PMID: 14701873
  46. 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
  47. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF.
    Cell. 2005 Jun 17;121(6):873-85 PMID: 15960975
  48. The bulk of the peripheral B-cell pool in mice is stable and not rapidly renewed from the bone marrow.
    Proc Natl Acad Sci U S A. 1990 Jun;87(12):4781-4 PMID: 2352948
  49. Mll fusions generated by Cre-loxP-mediated de novo translocations can induce lineage reassignment in tumorigenesis.
    EMBO J. 2005 Sep 7;24(17):3136-46 PMID: 16096649
  50. MLL2: A new mammalian member of the trx/MLL family of genes.
    Genomics. 1999 Jul 15;59(2):187-92 PMID: 10409430
  51. Active genes are tri-methylated at K4 of histone H3.
    Nature. 2002 Sep 26;419(6905):407-11 PMID: 12353038
  52. Leukemic transformation of hematopoietic progenitors by MLL-GAS7 in the absence of Hoxa7 or Hoxa9.
    Blood. 2004 Apr 15;103(8):3192-9 PMID: 15070702
Article Info
Journal
Cell stem cell
Abbr.
Cell Stem Cell
ISSN
1875-9777
DOI
10.1016/j.stem.2007.05.019
Published
2007-09-13
Pages
324-37
Language
English
Region
United States
NLM ID
101311472
PMCID
PMC2234224
Subset
IM
Grants
NIDDK NIH HHS · K01 DK067119-04 · United States
NCRR NIH HHS · P20 RR016437 · United States
NIDDK NIH HHS · DK067119 · United States
NHLBI NIH HHS · R01 HL090036 · United States
NIDDK NIH HHS · K01 DK067119 · United States
NHLBI NIH HHS · R01 HL090036-01A2 · United States
NIAID NIH HHS · R01 AI051427 · United States
External Links
PubMed source DOI: 10.1016/j.stem.2007.05.019 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: product@genelibs.com

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