2009 Fiscal Year Final Research Report
Development of model and targeted therapy for BCR-ABL positive leukemia
| Project/Area Number |
20890097
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| Research Category |
Grant-in-Aid for Young Scientists (Start-up)
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| Allocation Type | Single-year Grants |
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| Research Field |
Hematology
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| Research Institution | Nagoya University |
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Principal Investigator |
MINAMI Yosuke Nagoya University, 医学部・附属病院, 医員 (60513752)
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| Project Period (FY) |
2008 – 2009
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| Keywords | 白血病 / 幹細胞 / キナーゼ阻害剤 / BCR-ABL / mTORシグナル |
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| Research Abstract |
Recent studies suggest that leukemia stem cells (LSCs) are responsible for relapse of leukemia following conventional or targeted agents and that aberrant activation of mTOR signaling is involved in LSCs. To examine mechanisms of drug resistance in Ph-positive (Ph+) LSCs and seek strategies to overcome the resistance, Ph+ leukemia patient cells were serially xenotransplanted into immunodeficient NOG mice. Spleen cells derived from leukemic NOG mice were co-cultured with S17 stromal cells (Minami, et al., PNAS, 2008) and treated with imatinib and the mTOR inhibitor, everolimus (RAD001). While quiescent CD34+ cells were insensitive to imatinib in spite of BCR-ABL-dephosphorylation, substantial cell death including CD34+ population was induced by treatment with nM level of everolimus. In imatinib-resistant Ph+ leukemia cell lines harboring T315I-mutation, everolimus induced cell death with low IC50 values in PI-exclusion assays. We are also investigating detailed biomarkers during the cell death such as phospho-S6K and in vivo effects of theses drugs. These results imply that treatment with everolimus can overcome the resistance to imatinib in Ph+ LSCs or T315I-mutated cells.
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Research Products
(26 results)
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[Journal Article] BCR-ABL-independent and RAS/MAPK pathway-dependent form of imatinib resistance in Ph-positive acute lymphoblastic leukemia cell line with activation of EphB42010
Author(s)
M Suzuki, A Abe, S Imagama, Y Nomura, R Tanizaki, Y Minami, F Hayakawa, Y Ito, A Katsumi, K Yamamoto, N Emi, H Kiyoi, T Naoe
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Journal Title
Eur J Haematol 84(3)
Pages: 229-238
Peer Reviewed
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[Journal Article] Irrespective of CD34 expression, lineage-committed cell fraction reconstitutes and reestablishes transformed Philadelphia chromosome-positive leukemia in NOG mice2010
Author(s)
R Tanizaki, Y Nomura, Y Miyata, Y Minami, A Abe, A Hanamura, M Sawa, M Murata, H Kiyoi, T Matsushita, T Naoe
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Journal Title
Cancer Sci 101(3)
Pages: 631-638
Peer Reviewed
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[Journal Article] KW-2449, a novel multi-kinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation2009
Author(s)
Y Shiotsu, H Kiyoi, Y Ishikawa, R Tanizaki, M Shimizu, H Umehara, K Ishii, Y Mori, K Ozeki, Y Minami, A Abe, H Maeda, T Akiyama, Y K, a, Y Sato, S Akinaga, T Naoe
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Journal Title
Blood 114(8)
Pages: 1607-1617
Peer Reviewed
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[Journal Article] Retention but significant reduction of BCR-ABL transcript in hematopoietic stem cells in chronic myeloid leukemia after imatinib therapy2008
Author(s)
A Abe, Y Minami, F Hayakawa, K Kitamura, Y Nomura, M Murata, A Katsumi, H Kiyoi, CHM Jamieson, JYJ Wang, T Naoe
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Journal Title
Int J Hematol 88(5)
Pages: 171-175
Peer Reviewed
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