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PMID: 17077147 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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 of the United States of America ·Vol. 103 ·No. 45 ·2006-11-07 ·Pages 16870-5

Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S

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.

MeSH Terms
Animals Antineoplastic Agents/therapeutic use B-Lymphocytes/enzymology Benzamides Blast Crisis/enzymology Burkitt Lymphoma/drug therapy,enzymology Cell Line, Tumor Cell Transformation, Neoplastic/metabolism Dasatinib Fusion Proteins, bcr-abl/antagonists & inhibitors Humans Imatinib Mesylate Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy,enzymology,genetics,pathology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Neoplastic Stem Cells/drug effects,enzymology Piperazines/therapeutic use Protein Kinase Inhibitors/therapeutic use Pyrimidines/therapeutic use Thiazoles/therapeutic use src-Family Kinases/deficiency,genetics,metabolism
Chemicals
Antineoplastic Agents Benzamides Piperazines Protein Kinase Inhibitors Pyrimidines Thiazoles Imatinib Mesylate Fusion Proteins, bcr-abl src-Family Kinases Dasatinib
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Hu Yiguo
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Swerdlow Sarah
Duffy Theodore M
Weinmann Roberto
Lee Francis Y
Li Shaoguang
References (29)
29 references, click to expand
  1. Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases.
    Blood. 2003 Jan 15;101(2):664-72 PMID: 12393636
  2. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.
    N Engl J Med. 2006 Jun 15;354(24):2531-41 PMID: 16775234
  3. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia.
    Nat Genet. 2004 May;36(5):453-61 PMID: 15098032
  4. Overriding imatinib resistance with a novel ABL kinase inhibitor.
    Science. 2004 Jul 16;305(5682):399-401 PMID: 15256671
  5. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML.
    N Engl J Med. 2004 Aug 12;351(7):657-67 PMID: 15306667
  6. Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML.
    Blood. 2004 Oct 15;104(8):2532-9 PMID: 15256422
  7. A tail of two src's: mutatis mutandis.
    Cell. 1987 Apr 10;49(1):1-4 PMID: 3030562
  8. p53 in chronic myelogenous leukemia in acute phase.
    Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6293-7 PMID: 2068108
  9. Absence of the human retinoblastoma gene product in the megakaryoblastic crisis of chronic myelogenous leukemia.
    Blood. 1991 Nov 1;78(9):2178-81 PMID: 1932738
  10. Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia.
    Blood. 1995 Apr 15;85(8):2013-6 PMID: 7718873
  11. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo.
    J Exp Med. 1996 Apr 1;183(4):1797-806 PMID: 8666936
  12. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow.
    Blood. 1998 Nov 15;92(10):3780-92 PMID: 9808572
  13. The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity.
    J Exp Med. 1999 May 3;189(9):1399-412 PMID: 10224280
  14. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl.
    Cancer Cell. 2005 Feb;7(2):129-41 PMID: 15710326
  15. The tyrosine kinase inhibitor STI571, like interferon-alpha, preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors from patients with chronic myeloid leukemia.
    Exp Hematol. 2000 May;28(5):551-7 PMID: 10812245
  16. The src homology 2 domain of Bcr/Abl is required for efficient induction of chronic myeloid leukemia-like disease in mice but not for lymphoid leukemogenesis or activation of phosphatidylinositol 3-kinase.
    Blood. 2001 Jan 1;97(1):4-13 PMID: 11133737
  17. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
    N Engl J Med. 2001 Apr 5;344(14):1031-7 PMID: 11287972
  18. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.
    N Engl J Med. 2001 Apr 5;344(14):1038-42 PMID: 11287973
  19. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.
    Science. 2001 Aug 3;293(5531):876-80 PMID: 11423618
  20. Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571.
    Blood. 2001 Nov 1;98(9):2808-16 PMID: 11675355
  21. Tyrosine phosphorylation of Grb2 by Bcr/Abl and epidermal growth factor receptor: a novel regulatory mechanism for tyrosine kinase signaling.
    EMBO J. 2001 Dec 3;20(23):6793-804 PMID: 11726515
  22. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro.
    Blood. 2002 Jan 1;99(1):319-25 PMID: 11756187
  23. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies.
    J Clin Oncol. 2002 Mar 15;20(6):1692-703 PMID: 11896121
  24. Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation.
    Blood. 2002 May 15;99(10):3792-800 PMID: 11986238
  25. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop.
    Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10700-5 PMID: 12149456
  26. Selective pyrrolo-pyrimidine inhibitors reveal a necessary role for Src family kinases in Bcr-Abl signal transduction and oncogenesis.
    Oncogene. 2002 Nov 21;21(53):8075-88 PMID: 12444544
  27. Punish the parent not the progeny.
    Blood. 2005 Mar 1;105(5):1862-6 PMID: 15528314
  28. Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia.
    Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6688-93 PMID: 16618932
  29. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571.
    Blood. 2003 Jan 15;101(2):690-8 PMID: 12509383
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0606509103
Published
2006-11-07
Epub
2006-00-31
Pages
16870-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1629087
Subset
IM
Grants
NCI NIH HHS · R01 CA114199 · United States
NCI NIH HHS · CA 114199 · United States
External Links
PubMed source DOI: 10.1073/pnas.0606509103 PMC Full Text View journal details
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