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Blood, Vol. 96 No. 3 (August 1), 2000: pp. 1070-1079

Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance

François Xavier Mahon, Michael W. N. Deininger, Beate Schultheis, Jérome Chabrol, Josy Reiffers, John M. Goldman, and Junia V. Melo

From the Department of Haematology, Imperial College School of Science, Technology and Medicine, Hammersmith Hospital, London, UK; and the Laboratoire Greffe de Moelle, Université Victor Segalen, Bordeaux, France.

Targeting the tyrosine kinase activity of Bcr-Abl with STI571 is an attractive therapeutic strategy in chronic myelogenous leukemia (CML). A few CML cell lines and primary progenitors are, however, resistant to this compound. We investigated the mechanism of this resistance in clones of the murine BaF/3 cells transfected with BCR-ABL and in 4 human cell lines from which sensitive (s) and resistant (r) clones were generated by various methods. Although the resistant cells were able to survive in the presence of STI571, their proliferation was approximately 30% lower than that of their sensitive counterparts in the absence of the compound. The concentration of STI571 needed for a 50% reduction in viable cells after a 3-day exposure was on average 10 times higher in the resistant (2-3 µmol/L) than in the sensitive (0.2-0.25 µmol/L) clones. The mechanism of resistance to STI571 varied among the cell lines. Thus, in Baf/BCR-ABL-r, LAMA84-r, and AR230-r, there was up-regulation of the Bcr-Abl protein associated with amplification of the BCR-ABL gene. In K562-r, there was no Bcr-Abl overexpression, but the IC50 for the inhibition of Bcr-Abl autophosphorylation was increased in the resistant clones. Sequencing of the Abl kinase domain revealed no mutations. The multidrug resistance P-glycoprotein (Pgp) was overexpressed in LAMA84-r, indicating that at least 2 mechanisms of resistance operate in this cell line. KCL22-r showed neither Bcr-Abl up-regulation nor a higher threshold for tyrosine kinase inhibition by STI571. We conclude that BCR-ABL-positive cells can evade the inhibitory effect of STI571 by different mechanisms, such as Bcr-Abl overexpression, reduced intake mediated by Pgp, and, possibly, acquisition of compensatory mutations in genes other than BCR-ABL.


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Related Letter in Blood Online:

Another possible mechanism of resistance to STI571
Zachary A. Knight;, Carlo Gambacorti-Passerini, Philipp le Coutre, Elena Tassi, and Holger Ruchatz
Blood 2000 96: 4003-4005. [Full Text] [PDF]



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Pharmacol. Rev., September 1, 2003; 55(3): 401 - 423.
[Abstract] [Full Text] [PDF]


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BloodHome page
N. Widmer, S. Colombo, T. Buclin, and L. A. Decosterd
Functional consequence of MDR1 expression on imatinib intracellular concentrations
Blood, August 1, 2003; 102(3): 1142 - 1142.
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BloodHome page
J. Cortes, F. Giles, S. O'Brien, D. Thomas, G. Garcia-Manero, M. B. Rios, S. Faderl, S. Verstovsek, A. Ferrajoli, E. J. Freireich, et al.
Result of high-dose imatinib mesylate in patients with Philadelphia chromosome--positive chronic myeloid leukemia after failure of interferon-{alpha}
Blood, July 1, 2003; 102(1): 83 - 86.
[Abstract] [Full Text] [PDF]


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Molecular Cancer TherapeuticsHome page
S. Kasibhatla and B. Tseng
Why Target Apoptosis in Cancer Treatment?
Mol. Cancer Ther., June 1, 2003; 2(6): 573 - 580.
[Abstract] [Full Text] [PDF]


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Clin. Cancer Res.Home page
J. A. Zonder, P. Pemberton, H. Brandt, A. N. Mohamed, and C. A. Schiffer
The Effect of Dose Increase of Imatinib Mesylate in Patients with Chronic or Accelerated Phase Chronic Myelogenous Leukemia with Inadequate Hematologic or Cytogenetic Response to Initial Treatment
Clin. Cancer Res., June 1, 2003; 9(6): 2092 - 2097.
[Abstract] [Full Text] [PDF]


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Stem CellsHome page
K. Ohmine, T. Nagai, T. Tarumoto, T. Miyoshi, K. Muroi, H. Mano, N. Komatsu, F. Takaku, and K. Ozawa
Analysis of Gene Expression Profiles in an Imatinib-Resistant Cell Line, KCL22/SR
Stem Cells, May 1, 2003; 21(3): 315 - 321.
[Abstract] [Full Text] [PDF]


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Clin. Cancer Res.Home page
A. N. Mohamed, P. Pemberton, J. Zonder, and C. A. Schiffer
The Effect of Imatinib Mesylate on Patients with Philadelphia Chromosome-positive Chronic Myeloid Leukemia with Secondary Chromosomal Aberrations
Clin. Cancer Res., April 1, 2003; 9(4): 1333 - 1337.
[Abstract] [Full Text] [PDF]


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BloodHome page
F.-X. Mahon, F. Belloc, V. Lagarde, C. Chollet, F. Moreau-Gaudry, J. Reiffers, J. M. Goldman, and J. V. Melo
MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models
Blood, March 15, 2003; 101(6): 2368 - 2373.
[Abstract] [Full Text] [PDF]


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Molecular Cancer TherapeuticsHome page
A. Nakajima, T. Tauchi, M. Sumi, W. R. Bishop, and K. Ohyashiki
Efficacy of SCH66336, a Farnesyl Transferase Inhibitor, in Conjunction with Imatinib against BCR-ABL-positive Cells
Mol. Cancer Ther., March 1, 2003; 2(3): 219 - 224.
[Abstract] [Full Text] [PDF]


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J. Pharmacol. Exp. Ther.Home page
H. Dai, P. Marbach, M. Lemaire, M. Hayes, and W. F. Elmquist
Distribution of STI-571 to the Brain Is Limited by P-Glycoprotein-Mediated Efflux
J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 1085 - 1092.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
L. Tatton, G. M. Morley, R. Chopra, and A. Khwaja
The Src-selective Kinase Inhibitor PP1 Also Inhibits Kit and Bcr-Abl Tyrosine Kinases
J. Biol. Chem., February 7, 2003; 278(7): 4847 - 4853.
[Abstract] [Full Text] [PDF]


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Clin. Cancer Res.Home page
C. Gambacorti-Passerini, M. Zucchetti, D. Russo, R. Frapolli, M. Verga, S. Bungaro, L. Tornaghi, F. Rossi, P. Pioltelli, E. Pogliani, et al.
{alpha}1 Acid Glycoprotein Binds to Imatinib (STI571) and Substantially Alters Its Pharmacokinetics in Chronic Myeloid Leukemia Patients
Clin. Cancer Res., February 1, 2003; 9(2): 625 - 632.
[Abstract] [Full Text] [PDF]


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BloodHome page
N. J. Donato, J. Y. Wu, J. Stapley, G. Gallick, H. Lin, R. Arlinghaus, and M. Talpaz
BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571
Blood, January 15, 2003; 101(2): 690 - 698.
[Abstract] [Full Text] [PDF]


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BloodHome page
H. M. Kantarjian, M. Talpaz, S. O'Brien, F. Giles, G. Garcia-Manero, S. Faderl, D. Thomas, J. Shan, M. B. Rios, and J. Cortes
Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia
Blood, January 15, 2003; 101(2): 473 - 475.
[Abstract] [Full Text] [PDF]


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ASH Education BookHome page
J. V. Melo, T. P. Hughes, and J. F. Apperley
Chronic Myeloid Leukemia
Hematology, January 1, 2003; 2003(1): 132 - 152.
[Abstract] [Full Text] [PDF]


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Mol Cancer ResHome page
J. M.L. Ebos, J. Tran, Z. Master, D. Dumont, J. V. Melo, E. Buchdunger, and R. S. Kerbel
Imatinib Mesylate (STI-571) Reduces Bcr-Abl-Mediated Vascular Endothelial Growth Factor Secretion in Chronic Myelogenous Leukemia
Mol. Cancer Res., December 1, 2002; 1(2): 89 - 95.
[Abstract] [Full Text] [PDF]


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Ann. Surg. Oncol.Home page
R. P. DeMatteo
The GIST of Targeted Cancer Therapy: A Tumor (Gastrointestinal Stromal Tumor), a Mutated Gene (c-kit), and a Molecular Inhibitor (STI571)
Ann. Surg. Oncol., November 1, 2002; 9(9): 831 - 839.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
C. Ricci, B. Scappini, V. Divoky, S. Gatto, F. Onida, S. Verstovsek, H. M. Kantarjian, and M. Beran
Mutation in the ATP-binding Pocket of the ABL Kinase Domain in an STI571-resistant BCR/ABL-positive Cell Line
Cancer Res., November 1, 2002; 62(21): 5995 - 5998.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
R. Nimmanapalli, E. O'Bryan, M. Huang, P. Bali, P. K. Burnette, T. Loughran, J. Tepperberg, R. Jove, and K. Bhalla
Molecular Characterization and Sensitivity of STI-571 (Imatinib Mesylate, Gleevec)-resistant, Bcr-Abl-positive, Human Acute Leukemia Cells to SRC Kinase Inhibitor PD180970 and 17-Allylamino-17-demethoxygeldanamycin
Cancer Res., October 15, 2002; 62(20): 5761 - 5769.
[Abstract] [Full Text] [PDF]


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Clin. Cancer Res.Home page
C. Yu, G. Krystal, P. Dent, and S. Grant
Flavopiridol Potentiates STI571-induced Mitochondrial Damage and Apoptosis in BCR-ABL-positive Human Leukemia Cells
Clin. Cancer Res., September 1, 2002; 8(9): 2976 - 2984.
[Abstract] [Full Text] [PDF]


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BloodHome page
O. G. Ottmann, B. J. Druker, C. L. Sawyers, J. M. Goldman, J. Reiffers, R. T. Silver, S. Tura, T. Fischer, M. W. Deininger, C. A. Schiffer, et al.
A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias
Blood, August 28, 2002; 100(6): 1965 - 1971.
[Abstract] [Full Text] [PDF]


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BloodHome page
A. F. List, K. J. Kopecky, C. L. Willman, D. R. Head, M. L. Slovak, D. Douer, S. R. Dakhil, and F. R. Appelbaum
Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase
Blood, August 13, 2002; 100(5): 1910 - 1912.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
D. Wisniewski, C. L. Lambek, C. Liu, A. Strife, D. R. Veach, B. Nagar, M. A. Young, T. Schindler, W. G. Bornmann, J. R. Bertino, et al.
Characterization of Potent Inhibitors of the Bcr-Abl and the c-Kit Receptor Tyrosine Kinases
Cancer Res., August 1, 2002; 62(15): 4244 - 4255.
[Abstract] [Full Text] [PDF]


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BloodHome page
C. Roche-Lestienne, V. Soenen-Cornu, N. Grardel-Duflos, J.-L. Lai, N. Philippe, T. Facon, P. Fenaux, and C. Preudhomme
Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment
Blood, July 18, 2002; 100(3): 1014 - 1018.
[Abstract] [Full Text] [PDF]


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BloodHome page
R. R. Hoover, F.-X. Mahon, J. V. Melo, and G. Q. Daley
Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336
Blood, July 18, 2002; 100(3): 1068 - 1071.
[Abstract] [Full Text] [PDF]


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BloodHome page
L. Luzzatto and J. V. Melo
Acquired resistance to imatinib mesylate: selection for pre-existing mutant cells
Blood, July 18, 2002; 100(3): 1105 - 1106.
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Stem CellsHome page
V. Desplat, J.-L. Faucher, F. X. Mahon, P. Dello Sbarba, V. Praloran, and Z. Ivanovic
Hypoxia Modifies Proliferation and Differentiation of CD34+ CML Cells
Stem Cells, July 1, 2002; 20(4): 347 - 354.
[Abstract] [Full Text] [PDF]


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BloodHome page
C. L. Sawyers, A. Hochhaus, E. Feldman, J. M. Goldman, C. B. Miller, O. G. Ottmann, C. A. Schiffer, M. Talpaz, F. Guilhot, M. W. N. Deininger, et al.
Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study
Blood, May 15, 2002; 99(10): 3530 - 3539.
[Abstract] [Full Text] [PDF]


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BloodHome page
M. Levis, J. Allebach, K.-F. Tse, R. Zheng, B. R. Baldwin, B. D. Smith, S. Jones-Bolin, B. Ruggeri, C. Dionne, and D. Small
A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo
Blood, May 13, 2002; 99(11): 3885 - 3891.
[Abstract] [Full Text] [PDF]


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BloodHome page
S. G. O'Brien, S. A. D. Vieira, S. Connors, N. Bown, J. Chang, R. Capdeville, and J. V. Melo
Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation
Blood, May 1, 2002; 99(9): 3465 - 3467.
[Abstract] [Full Text] [PDF]


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BloodHome page
S. Branford, Z. Rudzki, S. Walsh, A. Grigg, C. Arthur, K. Taylor, R. Herrmann, K. P. Lynch, and T. P. Hughes
High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance
Blood, May 1, 2002; 99(9): 3472 - 3475.
[Abstract] [Full Text] [PDF]


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The OncologistHome page
M. O'Dwyer
Multifaceted Approach to the Treatment of Bcr-Abl-Positive Leukemias
Oncologist, April 1, 2002; 7(90001): 30 - 38.
[Abstract] [Full Text] [PDF]


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BloodHome page
M. Talpaz, R. T. Silver, B. J. Druker, J. M. Goldman, C. Gambacorti-Passerini, F. Guilhot, C. A. Schiffer, T. Fischer, M. W. N. Deininger, A. L. Lennard, et al.
Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study
Blood, March 15, 2002; 99(6): 1928 - 1937.
[Abstract] [Full Text] [PDF]


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BloodHome page
B. Schultheis, M. Carapeti-Marootian, A. Hochhaus, A. Weibeta er, J. M. Goldman, and J. V. Melo
Overexpression of SOCS-2 in advanced stages of chronic myeloid leukemia: possible inadequacy of a negative feedback mechanism
Blood, March 1, 2002; 99(5): 1766 - 1775.
[Abstract] [Full Text] [PDF]


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BloodHome page
W.-K. Hofmann, L. C. Jones, N. A. Lemp, S. de Vos, H. Gschaidmeier, D. Hoelzer, O. G. Ottmann, and H. P. Koeffler
Ph+ acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation
Blood, March 1, 2002; 99(5): 1860 - 1862.
[Abstract] [Full Text] [PDF]


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NEJMHome page
D. G. Savage and K. H. Antman
Imatinib Mesylate -- A New Oral Targeted Therapy
N. Engl. J. Med., February 28, 2002; 346(9): 683 - 693.
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BloodHome page
B. M. F. Mow, J. Chandra, P. A. Svingen, C. G. Hallgren, E. Weisberg, T. J. Kottke, V. L. Narayanan, M. R. Litzow, J. D. Griffin, E. A. Sausville, et al.
Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro
Blood, January 15, 2002; 99(2): 664 - 671.
[Abstract] [Full Text] [PDF]


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BloodHome page
H. G. Jorgensen, M. A. Elliott, E. K. Allan, C. E. Carr, T. L. Holyoake, and K. D. Smith
alpha 1-Acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571
Blood, January 15, 2002; 99(2): 713 - 715.
[Abstract] [Full Text] [PDF]


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JCOHome page
M. J. Mauro, M. O'Dwyer, M. C. Heinrich, and B. J. Druker
STI571: A Paradigm of New Agents for Cancer Therapeutics
J. Clin. Oncol., January 1, 2002; 20(1): 325 - 334.
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Cancer Res.Home page
C. Yu, G. Krystal, L. Varticovksi, R. McKinstry, M. Rahmani, P. Dent, and S. Grant
Pharmacologic Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase/Mitogen-activated Protein Kinase Inhibitors Interact Synergistically with STI571 to Induce Apoptosis in Bcr/Abl-expressing Human Leukemia Cells
Cancer Res., January 1, 2002; 62(1): 188 - 199.
[Abstract] [Full Text] [PDF]



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