Abstract
In Ph-positive (Ph{sup +}) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph{sup +} acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ{sup null} (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G{sub 0} cells in the CD34{sup +}CD38{sup −} population compared with the CD34{sup +}CD38{sup +} and CD34{sup −} populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34{sup +}CD38{sup −} population than in the other populations. Although slow-cycling G{sub 0} cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34{sup +}CD38{sup −} population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34{sup +} cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph{sup +}
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Kuwatsuka, Y;
Minami, M;
Minami, Y;
Sugimoto, K;
Hayakawa, F;
Miyata, Y;
Abe, A;
[1]
Goff, D J;
[2]
Kiyoi, H;
[3]
Naoe, T
[1]
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya (Japan)
- Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA (United States)
- Department of Infectious Diseases, Nagoya University Hospital, Nagoya (Japan)
Citation Formats
Kuwatsuka, Y, Minami, M, Minami, Y, Sugimoto, K, Hayakawa, F, Miyata, Y, Abe, A, Goff, D J, Kiyoi, H, and Naoe, T.
The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells.
United Kingdom: N. p.,
2011.
Web.
doi:10.1038/BCJ.2011.16.
Kuwatsuka, Y, Minami, M, Minami, Y, Sugimoto, K, Hayakawa, F, Miyata, Y, Abe, A, Goff, D J, Kiyoi, H, & Naoe, T.
The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells.
United Kingdom.
https://doi.org/10.1038/BCJ.2011.16
Kuwatsuka, Y, Minami, M, Minami, Y, Sugimoto, K, Hayakawa, F, Miyata, Y, Abe, A, Goff, D J, Kiyoi, H, and Naoe, T.
2011.
"The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells."
United Kingdom.
https://doi.org/10.1038/BCJ.2011.16.
@misc{etde_22342974,
title = {The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells}
author = {Kuwatsuka, Y, Minami, M, Minami, Y, Sugimoto, K, Hayakawa, F, Miyata, Y, Abe, A, Goff, D J, Kiyoi, H, and Naoe, T}
abstractNote = {In Ph-positive (Ph{sup +}) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph{sup +} acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ{sup null} (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G{sub 0} cells in the CD34{sup +}CD38{sup −} population compared with the CD34{sup +}CD38{sup +} and CD34{sup −} populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34{sup +}CD38{sup −} population than in the other populations. Although slow-cycling G{sub 0} cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34{sup +}CD38{sup −} population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34{sup +} cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph{sup +} leukemia due to quiescence.}
doi = {10.1038/BCJ.2011.16}
journal = []
issue = {5}
volume = {1}
journal type = {AC}
place = {United Kingdom}
year = {2011}
month = {May}
}
title = {The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells}
author = {Kuwatsuka, Y, Minami, M, Minami, Y, Sugimoto, K, Hayakawa, F, Miyata, Y, Abe, A, Goff, D J, Kiyoi, H, and Naoe, T}
abstractNote = {In Ph-positive (Ph{sup +}) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph{sup +} acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rγ{sup null} (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G{sub 0} cells in the CD34{sup +}CD38{sup −} population compared with the CD34{sup +}CD38{sup +} and CD34{sup −} populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34{sup +}CD38{sup −} population than in the other populations. Although slow-cycling G{sub 0} cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34{sup +}CD38{sup −} population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34{sup +} cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph{sup +} leukemia due to quiescence.}
doi = {10.1038/BCJ.2011.16}
journal = []
issue = {5}
volume = {1}
journal type = {AC}
place = {United Kingdom}
year = {2011}
month = {May}
}