Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival.

Cancer stem cells (CSCs) are responsible for the initiation and maintenance of some types of cancer, suggesting that inhibition of these cells may limit disease progression and relapse. Unfortunately, few CSC-specific genes have been identified. Here, we determined that the gene encoding arachidonate 15-lipoxygenase (Alox15/15-LO) is essential for the survival of leukemia stem cells (LSCs) in a murine model of BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL was unable to induce CML in mice. Furthermore, Alox15 deletion impaired LSC function by affecting cell division and apoptosis, leading to an eventual depletion of LSCs. Moreover, chemical inhibition of 15-LO function impaired LSC function and attenuated CML in mice. The defective CML phenotype in Alox15-deficient animals was rescued by depleting the gene encoding P-selectin, which is upregulated in Alox15-deficient animals. Both deletion and overexpression of P-selectin affected the survival of LSCs. In human CML cell lines and CD34+ cells, knockdown of Alox15 or inhibition of 15-LO dramatically reduced survival. Loss of Alox15 altered expression of PTEN, PI3K/AKT, and the transcription factor ICSBP, which are known mediators of cancer pathogenesis. These results suggest that ALOX15 has potential as a therapeutic target for eradicating LSCs in CML.

[1]  B. Druker,et al.  KIT signaling governs differential sensitivity of mature and primitive CML progenitors to tyrosine kinase inhibitors. , 2013, Cancer research.

[2]  Jessica M. Rusert,et al.  A Pan-BCL2 inhibitor renders bone-marrow-resident human leukemia stem cells sensitive to tyrosine kinase inhibition. , 2013, Cell stem cell.

[3]  Michael R. Green,et al.  The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells , 2012, Nature Genetics.

[4]  C. Peng,et al.  LSK Derived LSK– Cells Have a High Apoptotic Rate Related to Survival Regulation of Hematopoietic and Leukemic Stem Cells , 2012, PloS one.

[5]  C. Peng,et al.  Functional Ramifications for the Loss of P-Selectin Expression on Hematopoietic and Leukemic Stem Cells , 2011, PloS one.

[6]  Liang Zhao,et al.  Hematopoietic stem cell function requires 12/15-lipoxygenase-dependent fatty acid metabolism. , 2010, Blood.

[7]  Takahiro Ito,et al.  Regulation of myeloid leukemia by the cell fate determinant Musashi , 2010, Nature.

[8]  Yukio Kondo,et al.  TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia , 2010, Nature.

[9]  C. Peng,et al.  PTEN is a tumor suppressor in CML stem cells and BCR-ABL-induced leukemias in mice. , 2010, Blood.

[10]  B. Leber,et al.  BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38- cells, through activation of protein kinase Cbeta. , 2009, Blood.

[11]  C. Peng,et al.  Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia , 2009, Nature Genetics.

[12]  M. Warmuth,et al.  Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. , 2008, Cancer cell.

[13]  I. Weissman,et al.  Stems Cells and the Pathways to Aging and Cancer , 2008, Cell.

[14]  R. Schneiter,et al.  Lipid signalling in disease , 2008, Nature Reviews Molecular Cell Biology.

[15]  T. Reya,et al.  Loss of β-Catenin Impairs the Renewal of Normal and CML Stem Cells In Vivo , 2007 .

[16]  J. McNamara.  Cancer Stem Cells , 2007, Methods in Molecular Biology.

[17]  C. Peng,et al.  Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I-induced leukemia and suppresses leukemic stem cells. , 2007, Blood.

[18]  P. Reddanna,et al.  Effect of 15-lipoxygenase metabolites, 15-(S)-HPETE and 15-(S)-HETE on chronic myelogenous leukemia cell line K-562: reactive oxygen species (ROS) mediate caspase-dependent apoptosis. , 2007, Biochemical pharmacology.

[19]  F. Lee,et al.  Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice , 2006, Proceedings of the National Academy of Sciences.

[20]  E. Puré,et al.  Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease , 2006, The Journal of experimental medicine.

[21]  V. O’Donnell,et al.  Inflammation and immune regulation by 12/15-lipoxygenases. , 2006, Progress in lipid research.

[22]  S. Morrison,et al.  Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells , 2006, Nature.

[23]  Hongyue Dai,et al.  Gene expression changes associated with progression and response in chronic myeloid leukemia. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Guido Marcucci,et al.  The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. , 2005, Cancer cell.

[25]  J. Dick,et al.  Cancer stem cells: lessons from leukemia. , 2005, Trends in cell biology.

[26]  S. Morrison,et al.  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. , 2005, Genes & development.

[27]  S. Morrison,et al.  Diverse mechanisms regulate stem cell self-renewal. , 2004, Current opinion in cell biology.

[28]  Yiguo Hu,et al.  Lack of the adhesion molecules P-selectin and intercellular adhesion molecule-1 accelerate the development of BCR/ABL-induced chronic myeloid leukemia-like myeloproliferative disease in mice. , 2004, Blood.

[29]  D. Fabbro,et al.  Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia , 2004, Nature Genetics.

[30]  G. Peltz,et al.  Regulation of Bone Mass in Mice by the Lipoxygenase Gene Alox15 , 2004, Science.

[31]  Michael F. Clarke,et al.  Applying the principles of stem-cell biology to cancer , 2003, Nature Reviews Cancer.

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

[33]  I. Weissman,et al.  A role for Wnt signalling in self-renewal of haematopoietic stem cells , 2003, Nature.

[34]  G. Sauvageau,et al.  Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells , 2003, Nature.

[35]  Irving L. Weissman,et al.  Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells , 2003, Nature.

[36]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[37]  S. Lowe,et al.  Tumor suppression by Ink4a-Arf: progress and puzzles. , 2003, Current opinion in genetics & development.

[38]  R. V. van Etten,et al.  Tyrosine phosphorylation of Grb2 by Bcr/Abl and epidermal growth factor receptor: a novel regulatory mechanism for tyrosine kinase signaling , 2001, The EMBO journal.

[39]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[40]  J. Taipale,et al.  The Hedgehog and Wnt signalling pathways in cancer , 2001, Nature.

[41]  M. Deininger,et al.  The tyrosine kinase inhibitor STI571, like interferon-α, preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors from patients with chronic myeloid leukemia , 2000 .

[42]  George Q. Daley,et al.  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 , 1999, The Journal of experimental medicine.

[43]  J. Dick,et al.  Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell , 1997, Nature Medicine.

[44]  M. Caligiuri,et al.  A cell initiating human acute myeloid leukaemia after transplantation into SCID mice , 1994, Nature.

[45]  Shaoguang Li,et al.  β-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia , 2009, Leukemia.

[46]  R. Arceci.  PML targeting eradicates quiescent leukaemia-initiating cells , 2009 .

[47]  Tannishtha Reya,et al.  Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia , 2009, Nature.

[48]  T. Reya,et al.  Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. , 2007, Cancer cell.

[49]  T. Holyoake,et al.  Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. , 2002, Blood.