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PMID: 19503090 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia.

Nature genetics ·Vol. 41 ·No. 7 ·2009-07-00 ·Pages 783-92

Chen Y, Hu Y, Zhang H, Peng C, Li S

Abstract

Targeting of cancer stem cells is believed to be essential for curative therapy of cancers, but supporting evidence is limited. Few selective target genes in cancer stem cells have been identified. Here we identify the arachidonate 5-lipoxygenase (5-LO) gene (Alox5) as a critical regulator for leukemia stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox5, BCR-ABL failed to induce CML in mice. This Alox5 deficiency caused impairment of the function of LSCs but not normal hematopoietic stem cells (HSCs) through affecting differentiation, cell division and survival of long-term LSCs (LT-LSCs), consequently causing a depletion of LSCs and a failure of CML development. Treatment of CML mice with a 5-LO inhibitor also impaired the function of LSCs similarly by affecting LT-LSCs, and prolonged survival. These results demonstrate that a specific target gene can be found in cancer stem cells and its inhibition can completely inhibit the function of these stem cells.

MeSH Terms
Animals Hematopoietic Stem Cells/metabolism Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics Mice Mice, Inbred C57BL Mice, Knockout Neoplastic Stem Cells/enzymology,metabolism
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Chen Yaoyu
Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Hu Yiguo
Zhang Haojian
Peng Cong
Li Shaoguang
References (45)
45 references, click to expand
  1. Selective inhibitors of 5-lipoxygenase reduce CML blast cell proliferation and induce limited differentiation and apoptosis.
    Leuk Res. 1995 Nov;19(11):789-801 PMID: 8551795
  2. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors.
    Cancer Cell. 2004 Dec;6(6):587-96 PMID: 15607963
  3. The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm.
    Nat Med. 2004 Sep;10(9):966-73 PMID: 15322539
  4. The Hedgehog and Wnt signalling pathways in cancer.
    Nature. 2001 May 17;411(6835):349-54 PMID: 11357142
  5. Identification of a cancer stem cell in human brain tumors.
    Cancer Res. 2003 Sep 15;63(18):5821-8 PMID: 14522905
  6. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.
    Nat Med. 1997 Jul;3(7):730-7 PMID: 9212098
  7. Gene expression changes associated with progression and response in chronic myeloid leukemia.
    Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2794-9 PMID: 16477019
  8. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells.
    Nature. 2003 May 15;423(6937):255-60 PMID: 12714970
  9. Cancer stem cells: lessons from leukemia.
    Trends Cell Biol. 2005 Sep;15(9):494-501 PMID: 16084092
  10. Lipid signalling in disease.
    Nat Rev Mol Cell Biol. 2008 Feb;9(2):162-76 PMID: 18216772
  11. The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity.
    J Exp Med. 1999 May 3;189(9):1399-412 PMID: 10224280
  12. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
    Nature. 2003 May 15;423(6937):302-5 PMID: 12714971
  13. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo.
    Cancer Cell. 2007 Dec;12(6):528-41 PMID: 18068630
  14. Stem cells, cancer, and cancer stem cells.
    Nature. 2001 Nov 1;414(6859):105-11 PMID: 11689955
  15. Leukotriene B4: metabolism and signal transduction.
    Arch Biochem Biophys. 2001 Jan 15;385(2):231-41 PMID: 11368003
  16. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells.
    Nature. 2006 May 25;441(7092):475-82 PMID: 16598206
  17. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro.
    Blood. 2002 Jan 1;99(1):319-25 PMID: 11756187
  18. Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene.
    Nature. 1994 Nov 10;372(6502):179-82 PMID: 7969451
  19. Inverse relationship between myeloid maturation and leukotriene C4 synthase expression in normal and leukemic myelopoiesis-consistent overexpression of the enzyme in myeloid cells from patients with chronic myeloid leukemia.
    Exp Hematol. 2003 Feb;31(2):122-30 PMID: 12591277
  20. Leukotriene production by fresh human bone marrow cells: evidence of altered lipoxygenase activity in chronic myelocytic leukemia.
    Exp Hematol. 1987 Feb;15(2):203-7 PMID: 3028851
  21. Cancer stem cells.
    N Engl J Med. 2006 Sep 21;355(12):1253-61 PMID: 16990388
  22. GATA1 function, a paradigm for transcription factors in hematopoiesis.
    Mol Cell Biol. 2005 Feb;25(4):1215-27 PMID: 15684376
  23. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation.
    Cancer Cell. 2008 Sep 9;14(3):238-49 PMID: 18772113
  24. Stems cells and the pathways to aging and cancer.
    Cell. 2008 Feb 22;132(4):681-96 PMID: 18295583
  25. Prospective identification of tumorigenic breast cancer cells.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8 PMID: 12629218
  26. 5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation.
    EMBO J. 2005 Jan 12;24(1):170-9 PMID: 15616590
  27. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice.
    Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16870-5 PMID: 17077147
  28. Transcriptional analysis of quiescent and proliferating CD34+ human hemopoietic cells from normal and chronic myeloid leukemia sources.
    Stem Cells. 2007 Dec;25(12):3111-20 PMID: 17717066
  29. The organization and consequences of eicosanoid signaling.
    J Clin Invest. 2003 Apr;111(8):1107-13 PMID: 12697726
  30. A role for Wnt signalling in self-renewal of haematopoietic stem cells.
    Nature. 2003 May 22;423(6938):409-14 PMID: 12717450
  31. Breast cancer cell-derived EMMPRIN stimulates fibroblast MMP2 release through a phospholipase A(2) and 5-lipoxygenase catalyzed pathway.
    Oncogene. 2002 Aug 22;21(37):5765-72 PMID: 12173047
  32. The tyrosine kinase inhibitor STI571, like interferon-alpha, preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors from patients with chronic myeloid leukemia.
    Exp Hematol. 2000 May;28(5):551-7 PMID: 10812245
  33. Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor.
    N Engl J Med. 1990 Dec 20;323(25):1745-8 PMID: 1701029
  34. Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I-induced leukemia and suppresses leukemic stem cells.
    Blood. 2007 Jul 15;110(2):678-85 PMID: 17395781
  35. Tyrosine phosphorylation of Grb2 by Bcr/Abl and epidermal growth factor receptor: a novel regulatory mechanism for tyrosine kinase signaling.
    EMBO J. 2001 Dec 3;20(23):6793-804 PMID: 11726515
  36. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.
    Nature. 1994 Feb 17;367(6464):645-8 PMID: 7509044
  37. Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties.
    Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5878-82 PMID: 17379664
  38. Applying the principles of stem-cell biology to cancer.
    Nat Rev Cancer. 2003 Dec;3(12):895-902 PMID: 14737120
  39. Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways.
    Genes Dev. 2005 Jun 15;19(12):1432-7 PMID: 15964994
  40. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia.
    Nat Genet. 2004 May;36(5):453-61 PMID: 15098032
  41. Diverse mechanisms regulate stem cell self-renewal.
    Curr Opin Cell Biol. 2004 Dec;16(6):700-7 PMID: 15530784
  42. FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation.
    Cell. 1997 Jul 11;90(1):109-19 PMID: 9230307
  43. 5-Lipoxygenase: regulation of expression and enzyme activity.
    Trends Biochem Sci. 2007 Jul;32(7):332-41 PMID: 17576065
  44. Leukemia stem cells in a genetically defined murine model of blast-crisis CML.
    Blood. 2007 Oct 1;110(7):2578-85 PMID: 17601986
  45. Tumor suppression by Ink4a-Arf: progress and puzzles.
    Curr Opin Genet Dev. 2003 Feb;13(1):77-83 PMID: 12573439
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.389
Published
2009-07-00
Epub
2009-00-07
Pages
783-92
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC2887745
Subset
IM
Grants
NCI NIH HHS · R01 CA122142-03 · United States
NCI NIH HHS · R01 CA114199-04 · United States
NCI NIH HHS · R01 CA114199-03 · United States
NCI NIH HHS · R01 CA114199 · United States
NCI NIH HHS · R01 CA122142 · United States
NCI NIH HHS · R01-CA114199 · United States
NCI NIH HHS · R01 CA122142-02 · United States
NCI NIH HHS · R01 CA122142-01A2 · United States
NCI NIH HHS · R01-CA122142 · United States
Databases
GEO
GSE10912
External Links
PubMed source DOI: 10.1038/ng.389 PMC Full Text View journal details
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