Abstract 4237: Foxo3a is essential for survival of leukemia-initiating cells in chronic myeloid leukemia

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8_Supplement), p.4237-4237
• Main Authors: Naka, Kazuhito, Hoshii, Takayuki, Muraguchi, Teruyuki, Tadokoro, Yuko, Ooshio, Takako, Motoyama, Noboru, Oshima, Masanobu, Hirao, Atsushi
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-4237

Chronic myelogenous leukemia (CML) is caused by 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 in chronic-phase CML are not off therapy due to resistance or intolerance. Recent studies have suggested that imatinib is a potent inhibitor of the production of differentiated leukemic cells, but does not deplete leukemia-initiating cells (LICs). To date, therapeutics that can eradicate CML LICs, however, have remained under investigation. To overcome these clinical problems, we here evaluated molecular mechanisms on survival of the CML LICs. We first generated a mouse CML model by using retroviral induction of BCR-ABL-ires-GFP gene into mouse immature hematopoietic cells, and the cells were subsequently transplanted into irradiated recipient mice. These experiments showed that CML LICs were highly enriched in c-Kit+Lin-Sca-1+ (KLS+) population in BCR-ABL+ CML cells, as previously reported. Unexpectedly, phosphorylation levels of Akt in CML LICs appeared to be lower than that in non-LICs, KLS- cells, despite it is widely believed that BCR-ABL 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 cells with nuclear localization of Foxo3a were enriched in the CML LICs, whereas non-LICs showed the cytoplasmic localization, suggesting that Foxo3a is activated via Akt inactivation in the CML LICs, but not in majority of CML cells. Serial transplantation experiments for CML LICs originated from Foxo3a-deficient mice and littermate wild-type mice indicated that Foxo3a-deficiency reduced lethality of recipient mice at 3rd transplantation. Although recipients that transplanted with wild-type LICs developed CML and acute lymphocytic leukemia (ALL) at 3rd transplantation, we did not observe development of ALL or CML in recipients of Foxo3a deficient LICs after 45 days post-3rd transplantation, suggesting that the Foxo3a deficient LICs lose their potential to generate malignancies. Furthermore, deficiency of Foxo3a led to enhanced efficiency in elimination of CML LICs in combination with imatinib treatment. These results