TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia.
Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a(+/+) and Foxo3a(-/-) mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-beta is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-beta inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-beta inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-beta-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.
Division of Molecular Genetics, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan. kazunaka@kenroku.kanazawa-u.ac.jp
Kazuhito
K
Naka
Takayuki
T
Hoshii
Teruyuki
T
Muraguchi
Yuko
Y
Tadokoro
Takako
T
Ooshio
Yukio
Y
Kondo
Shinji
S
Nakao
Noboru
N
Motoyama
Atsushi
A
Hirao
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001549:Benzamides; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D001549:Benzamides; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016212:Transforming Growth Factor beta; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt