Leukemic Stem Cell Labeling System by Nucleostemin Prompter EGFP

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					   FoxO3a is essential for survival of chronic myeloid leukemia-initiating cells

   Naka Kazuhito1, Noboru Motoyama2, Atsushi Hirao1
   (1 Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, 2 Department of
   Geriatric Medicine, National Institute for Longevity Sciences, National Center for Gerontology and

    Chronic myelogenous leukemia (CML) is attributed to a defined genetic abnormality, BCR-ABL, a
    constitutively active protein tyrosine kinase. Although the introduction of imatinib, a small molecule
    inhibitor of ABL, represented a breakthrough in the treatment of CML, major part of patients treated
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    in chronic-phase CML are not offNumber: Single. resistance or intolerance. Recent studies have
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    suggested that imatinib is a potent inhibitorin everyproduction of differentiated leukemic cells, but
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    does not deplete leukemic stem cells. To date, therapeutics that can eradicate CML-initiating cells,
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    however, have remained under investigation. To overcomepoints. clinical problems, we here
    evaluated molecular mechanisms on survival of the CML-initiating cells. We first generated a mouse
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    CML model by using retroviral induction of BCR-ABL-ires-GFP gene into mouse immature
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   hematopoietic aligned to the left. were subsequently transplanted into irradiated recipient mice. The
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   transplantation experiments showed that CML-initiating cells were highly enriched in
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   c-Kit+Lin-Sca-1+ (KLS+) population in BCR-ABL+ CML cells, as previously described.
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   Unexpectedly, phosphorylation level of Akt in KLS+ population as CML-initiating cells appeared to
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   be lower than that in non- the left cells, KLS- cells, despite it is widely believed that BCR-ABL
     Abstract text :aligned to initiating
   induces activation of Akt signal. Since Forkhead O (Foxo) transcription factors, which are important
   downstream targets of PI3K-Akt signaling, are essential for the maintenance of self-renewal capacity
   of normal HSCs, we focused on analysis of Foxo3a in CML. Consistent with Akt phosphorylation
   status, we found that approximately 40% of CML KLS+ showed nuclear localization of Foxo3a,
   whereas majority of KLS- cells showed the cytoplasmic localization, suggesting that Foxo3a is
   activated via Akt inactivation in the rare CML-initiating cells, but not in majority of CML cells.
   Serial transplantation experiments for CML-initiating cells originated from Foxo3a-deficient mice
   and littermate wild-type mice indicated that Foxo3a-deficiency attenuated the ability of
   CML-initiating cells to develop leukemia at third round transplantation experiments. Number of
   Annexin-V+ cells was higher in the Foxo3a-deficient CML-initiating cells than those seen in
   wild-type CML-initiating cells in vivo. Furthermore, deficiency of Foxo3a led to enhanced efficiency
   in elimination of CML-initiating cells in combination with imatinib treatment. These results
   demonstrate a critical role of Foxo pathway in survival of drug-resistant CML-initiating cells, and
   provide a novel therapeutics approach for CML patients by suppression of FOXO signaling.