DOI: 10.1073/pnas.0606509103. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph <sup>+</sup> leukemia in mice

Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph + leukemia in mice

10.1073/pnas.0606509103

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

It is generally believed that shutting down the kinase activity of BCR-ABL by imatinib will completely inhibit its functions, leading to inactivation of its downstream signaling pathways and cure of the disease. Imatinib is highly effective at treating human Philadelphia chromosome-positive (Ph + ) chronic myeloid leukemia (CML) in chronic phase but not Ph + B cell acute lymphoblastic leukemia (B-ALL) and CML blast crisis. We find that SRC kinases activated by BCR-ABL remain fully active in imatinib-treated mouse leukemic cells, suggesting that imatinib does not inactivate all BCR-ABL-activated signaling pathways. This SRC pathway is essential for leukemic cells to survive imatinib treatment and for CML transition to lymphoid blast crisis. Inhibition of both SRC and BCR-ABL kinase activities by dasatinib affords complete B-ALL remission. However, curing B-ALL and CML mice requires killing leukemic stem cells insensitive to both imatinib and dasatinib. Besides BCR-ABL and SRC kinases, stem cell pathways must be targeted for curative therapy of Ph + leukemia.

Bibliography

Hu, Y., Swerdlow, S., Duffy, T. M., Weinmann, R., Lee, F. Y., & Li, S. (2006). Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph + leukemia in mice. Proceedings of the National Academy of Sciences, 103(45), 16870â16875.

Authors 6

Yiguo Hu (first)
Sarah Swerdlow (additional)
Theodore M. Duffy (additional)
Roberto Weinmann (additional)
Francis Y. Lee (additional)
Shaoguang Li (additional)

References 29 Referenced 222

Dates

Type	When
Created	18 years, 10 months ago (Nov. 2, 2006, 8:25 a.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 3:50 p.m.)
Indexed	8 months ago (Dec. 30, 2024, 1:14 p.m.)
Issued	18 years, 9 months ago (Nov. 7, 2006)
Published	18 years, 9 months ago (Nov. 7, 2006)
Published Online	18 years, 9 months ago (Nov. 7, 2006)
Published Print	18 years, 9 months ago (Nov. 7, 2006)

Funders 0

None

BibTeX

@article{Hu_2006, title={Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph + leukemia in mice}, volume={103}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0606509103}, DOI={10.1073/pnas.0606509103}, number={45}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Hu, Yiguo and Swerdlow, Sarah and Duffy, Theodore M. and Weinmann, Roberto and Lee, Francis Y. and Li, Shaoguang}, year={2006}, month=nov, pages={16870–16875} }

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  "abstract": "<jats:p>\n            It is generally believed that shutting down the kinase activity of BCR-ABL by imatinib will completely inhibit its functions, leading to inactivation of its downstream signaling pathways and cure of the disease. Imatinib is highly effective at treating human Philadelphia chromosome-positive (Ph\n            <jats:sup>+</jats:sup>\n            ) chronic myeloid leukemia (CML) in chronic phase but not Ph\n            <jats:sup>+</jats:sup>\n            B cell acute lymphoblastic leukemia (B-ALL) and CML blast crisis. We find that SRC kinases activated by BCR-ABL remain fully active in imatinib-treated mouse leukemic cells, suggesting that imatinib does not inactivate all BCR-ABL-activated signaling pathways. This SRC pathway is essential for leukemic cells to survive imatinib treatment and for CML transition to lymphoid blast crisis. Inhibition of both SRC and BCR-ABL kinase activities by dasatinib affords complete B-ALL remission. However, curing B-ALL and CML mice requires killing leukemic stem cells insensitive to both imatinib and dasatinib. Besides BCR-ABL and SRC kinases, stem cell pathways must be targeted for curative therapy of Ph\n            <jats:sup>+</jats:sup>\n            leukemia.\n          </jats:p>",
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