Expression of a Src Family Kinase in Chronic Myelogenous Leukemia Cells Induces Resistance to Imatinib in a Kinase-dependent Manner

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 May 11

PMID 20452982

Citations 35

Authors

Teodora Pene-Dumitrescu

Thomas E Smithgall

Affiliations

Soon will be listed here.

Abstract

The Bcr-Abl kinase inhibitor imatinib is remarkably effective in chronic myelogenous leukemia (CML), although drug resistance is an emerging problem. Myeloid Src family kinases such as Hck and Lyn are often overexpressed in imatinib-resistant CML cells that lack Bcr-Abl mutations. Here we tested whether Hck overexpression is sufficient to induce imatinib resistance using both wild-type Hck and a mutant (Hck-T338A) that is uniquely sensitive to the pyrazolo-pyrimidine inhibitor, NaPP1. Expression of either kinase in K562 CML cells caused resistance to imatinib-induced apoptosis and inhibition of soft-agar colony formation. Treatment with NaPP1 restored sensitivity to imatinib in cells expressing T338A but not wild-type Hck, demonstrating that resistance requires Hck kinase activity. NaPP1 also reduced Hck-mediated phosphorylation of Bcr-Abl at sites that may affect imatinib sensitivity exclusively in cells expressing Hck-T338A. These data show that elevated Src family kinase activity is sufficient to induce imatinib resistance through a mechanism that may involve phosphorylation of Bcr-Abl.

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References

Schindler T, Bornmann W, Pellicena P, Miller W, Clarkson B, Kuriyan J . Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science. 2000; 289(5486):1938-42. DOI: 10.1126/science.289.5486.1938. View

Faderl S, Talpaz M, Estrov Z, OBrien S, Kurzrock R, Kantarjian H . The biology of chronic myeloid leukemia. N Engl J Med. 1999; 341(3):164-72. DOI: 10.1056/NEJM199907153410306. View

Klejman A, Schreiner S, Nieborowska-Skorska M, Slupianek A, Wilson M, Smithgall T . The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J. 2002; 21(21):5766-74. PMC: 131059. DOI: 10.1093/emboj/cdf562. View

Briggs S, Smithgall T . SH2-kinase linker mutations release Hck tyrosine kinase and transforming activities in Rat-2 fibroblasts. J Biol Chem. 1999; 274(37):26579-83. DOI: 10.1074/jbc.274.37.26579. View

Azam M, Seeliger M, Gray N, Kuriyan J, Daley G . Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat Struct Mol Biol. 2008; 15(10):1109-18. PMC: 2575426. DOI: 10.1038/nsmb.1486. View

Wu J, Meng F, Kong L, Peng Z, Ying Y, Bornmann W . Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst. 2008; 100(13):926-39. PMC: 2902818. DOI: 10.1093/jnci/djn188. View

Porter M, Schindler T, Kuriyan J, Miller W . Reciprocal regulation of Hck activity by phosphorylation of Tyr(527) and Tyr(416). Effect of introducing a high affinity intramolecular SH2 ligand. J Biol Chem. 2000; 275(4):2721-6. DOI: 10.1074/jbc.275.4.2721. View

Kirchner D, Duyster J, Ottmann O, Schmid R, Bergmann L, Munzert G . Mechanisms of Bcr-Abl-mediated NF-kappaB/Rel activation. Exp Hematol. 2003; 31(6):504-11. DOI: 10.1016/s0301-472x(03)00069-9. View

Gorre M, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao P . Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001; 293(5531):876-80. DOI: 10.1126/science.1062538. View

10.

LOZZIO B, Lozzio C, Bamberger E, Feliu A . A multipotential leukemia cell line (K-562) of human origin. Proc Soc Exp Biol Med. 1981; 166(4):546-50. DOI: 10.3181/00379727-166-41106. View

11.

Druker B, Guilhot F, OBrien S, Gathmann I, Kantarjian H, Gattermann N . Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006; 355(23):2408-17. DOI: 10.1056/NEJMoa062867. View

12.

Goga A, McLaughlin J, Afar D, Saffran D, Witte O . Alternative signals to RAS for hematopoietic transformation by the BCR-ABL oncogene. Cell. 1995; 82(6):981-8. DOI: 10.1016/0092-8674(95)90277-5. View

13.

Meyn 3rd M, Wilson M, Abdi F, Fahey N, Schiavone A, Wu J . Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. J Biol Chem. 2006; 281(41):30907-16. DOI: 10.1074/jbc.M605902200. View

14.

Bishop A, Shah K, Liu Y, Witucki L, Kung C, Shokat K . Design of allele-specific inhibitors to probe protein kinase signaling. Curr Biol. 1998; 8(5):257-66. DOI: 10.1016/s0960-9822(98)70198-8. View

15.

Donato N, Wu J, Stapley J, Gallick G, Lin H, Arlinghaus R . BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003; 101(2):690-8. DOI: 10.1182/blood.V101.2.690. View

16.

Azam M, Latek R, Daley G . Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell. 2003; 112(6):831-43. DOI: 10.1016/s0092-8674(03)00190-9. View

17.

Goldman J, Melo J . Chronic myeloid leukemia--advances in biology and new approaches to treatment. N Engl J Med. 2003; 349(15):1451-64. DOI: 10.1056/NEJMra020777. View

18.

Rix U, Hantschel O, Durnberger G, Remsing Rix L, Planyavsky M, Fernbach N . Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007; 110(12):4055-63. DOI: 10.1182/blood-2007-07-102061. View

19.

Plattner R, Kadlec L, DeMali K, Kazlauskas A, Pendergast A . c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF. Genes Dev. 1999; 13(18):2400-11. PMC: 317022. DOI: 10.1101/gad.13.18.2400. View

20.

Warmuth M, Druker B, Emmerich B, Hallek M . Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells. Cancer Res. 1996; 56(15):3589-96. View