Abstract
In Philadelphia chromosome-positive (Ph+) leukemia BCR/ABL induces the leukemic phenotype. Targeted inhibition of BCR/ABL by kinase inhibitors leads to complete remission. However, patients with advanced Ph+ leukemia relapse and acquire resistance, mainly due to point mutations in BCR/ABL. The ‘gatekeeper mutation’ T315I is responsible for a general resistance to small molecules. It seems not only to decrease the affinity for kinase inhibitors, but to also confer additional features to the leukemogenic potential of BCR/ABL. To determine the role of T315I in resistance to the inhibition of oligomerization and in the leukemogenic potential of BCR/ABL, we investigated its influence on loss-of-function mutants with regard to the capacity to mediate factor independence. Here, we show that T315I (i) requires autophosphorylation at tyrosine 177 in the BCR-portion to mediate resistance against the inhibition of oligomerization; (ii) restores the capacity to mediate factor-independent growth of loss-of-function mutants due to an increase in or activation of ABL-kinase; (iii) leads to phosphorylation of endogenous BCR, suggesting aberrant substrate activation by BCR/ABL harboring the T315I mutation. These data show that T315I confers additional leukemogenic activity to BCR/ABL, which might explain the clinical behavior of patients with BCR/ABL–T315I-positive blasts.
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References
Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM . The biology of chronic myeloid leukemia. N Engl J Med 1999; 341: 164–172.
Lugo TG, Pendergast AM, Muller AJ, Witte ON . Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990; 247: 1079–1082.
Deininger MW, Goldman JM, Lydon N, Melo JV . The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 1997; 90: 3691–3698.
Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–566.
Weisberg E, Griffin JD . Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood 2000; 95: 3498–3505.
Ramirez P, DiPersio JF . Therapy options in imatinib failures. Oncologist 2008; 13: 424–434.
Cowan-Jacob SW, Guez V, Fendrich G, Griffin JD, Fabbro D, Furet P et al. Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. Mini Rev Med Chem 2004; 4: 285–299.
Deininger M . Resistance to imatinib: mechanisms and management. J Natl Compr Canc Netw 2005; 3: 757–768.
Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002; 2: 117–125.
Druker BJ . Translation of the Philadelphia chromosome into therapy for CML. Blood 2008; 112: 4808–4817.
Beissert T, Puccetti E, Bianchini A, Güller S, Boehrer S, Hoelzer D et al. Targeting of the N-terminal coiled coil oligomerization interface of BCR interferes with the transformation potential of BCR-ABL and increases sensitivity to STI571. Blood 2003; 102: 2985–2993.
Beissert T, Hundertmark A, Kaburova V, Travaglini L, Mian AA, Nervi C et al. Targeting of the N-terminal coiled coil oligomerization interface by a helix-2 peptide inhibits unmutated and imatinib-resistant BCR/ABL. Int J Cancer 2008; 122: 2744–2752.
Puccetti E, Güller S, Orleth A, Brüggenolte N, Hoelzer D, Ottmann OG et al. BCR-ABL mediates arsenic trioxide-induced apoptosis independently of its aberrant kinase activity. Cancer Res 2000; 60: 3409–3413.
Griswold IJ, MacPartlin M, Bumm T, Goss VL, O'Hare T, Lee KA et al. Kinase domain mutants of Bcr-Abl exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity to imatinib. Mol Cell Biol 2006; 26: 6082–6093.
Zheng X, Beissert T, Kukoc-Zivojnov N, Puccetti E, Altschmied J, Strolz C et al. Gamma-catenin contributes to leukemogenesis induced by AML-associated translocation products by increasing the self-renewal of very primitive progenitor cells. Blood 2004; 103: 3535–3543.
Barilá D, Superti-Furga G . An intramolecular SH3-domain interaction regulates c-Abl activity. Nat Genet 1998; 18: 280–282.
Franz WM, Berger P, Wang JY . Deletion of an N-terminal regulatory domain of the c-abl tyrosine kinase activates its oncogenic potential. EMBO J 1989; 8: 137–147.
Laurent E, Talpaz M, Kantarjian H, Kurzrock R . The BCR gene and philadelphia chromosome-positive leukemogenesis. Cancer Res 2001; 61: 2343–2355.
Azam M, Seeliger MA, Gray NS, Kuriyan J, Daley GQ . Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat Struct Mol Biol 2008; 15: 1109–1118.
Acknowledgements
This project was supported by a grant from Deutsche Forschungsgemeinschaft (DFG-RU 728/3-1) to MR. MR is further funded by grants from Alfred und Angelika Gutermuth Foundation, Deutsche Krebshilfe e.V. (DKH-107063 and DKH-107741) and Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS - R 07/27f).
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Mian, A., Schüll, M., Zhao, Z. et al. The gatekeeper mutation T315I confers resistance against small molecules by increasing or restoring the ABL-kinase activity accompanied by aberrant transphosphorylation of endogenous BCR, even in loss-of-function mutants of BCR/ABL. Leukemia 23, 1614–1621 (2009). https://doi.org/10.1038/leu.2009.69
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DOI: https://doi.org/10.1038/leu.2009.69
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