Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pushing the limits of targeted therapy in chronic myeloid leukaemia

Nature Reviews Cancer volume 12, pages 513–526 (2012)Cite this article

Subjects

A Corrigendum to this article was published on 15 November 2012

This article has been updated

Key Points

  • Small-molecule BCR-ABL1 tyrosine kinase inhibitors (TKIs) have fundamentally improved the treatment of chronic myeloid leukaemia (CML) and have become a paradigm for molecularly targeted therapy, but they fail to kill leukaemic stem cells (LSCs).

  • BCR-ABL1-dependent resistance to currently approved TKIs typically involves single point mutations within the BCR-ABL1 tyrosine kinase domain that interfere with drug binding.

  • Third-generation TKIs that comprehensively cover single BCR-ABL1 mutants, including the T315I mutant (BCR-ABL1T315I), are in development. With respect to resistance, these TKIs are vulnerable to certain compound mutations (two or more mutations in the same BCR-ABL1 molecule) in in vitro model systems. The extent to which BCR-ABL1 compound mutation-based resistance tempers the effectiveness of third-generation TKIs in the clinical setting remains to be established.

  • BCR-ABL1-independent TKI resistance occurs despite effective inhibition of BCR-ABL1 kinase activity.

  • CML stem cells may rely on pathways similar to those responsible for BCR-ABL1-independent TKI resistance.

  • Other crucial targets in addition to BCR-ABL1 will probably need to be inhibited in both cases. Candidate pathways include Hedgehog, WNT–β-catenin, PP2A and transforming growth factor-β (TGFβ)–Forkhead box protein O3 (FOXO3A)–BCL-6.

Abstract

Tyrosine kinase inhibitor (TKI) therapy targeting the BCR-ABL1 kinase is effective against chronic myeloid leukaemia (CML), but is not curative for most patients. Minimal residual disease (MRD) is thought to reside in TKI-insensitive leukaemia stem cells (LSCs) that are not fully addicted to BCR-ABL1. Recent conceptual advances in both CML biology and therapeutic intervention have increased the potential for the elimination of CML cells, including LSCs, through simultaneous inhibition of BCR-ABL1 and other newly identified, crucial targets.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Two independent clinical evaluations of first-line use of nilotinib or dasatinib compared with imatinib for newly diagnosed CML.
Figure 2: A partially overlapping network of BCR-ABL1 kinase domain mutations confer resistance to certain TKIs.
Figure 3: Targeting opportunities in CML cells.

Change history

  • 15 November 2012

    On page 521 of this article, the passage discussing β-catenin as a regulator of gene expression in chronic myeloid leukaemia should have cited the following article alongside reference 118: Radich, J. P. et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc. Natl Acad. Sci. USA 103, 2794–2799 (2006). This has now been added as reference 168.

References

  1. Ren, R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nature Rev. Cancer 5, 172–183 (2005).

    CAS  Google Scholar 

  2. Rubbi, L. et al. Global phosphoproteomics reveals crosstalk between Bcr-Abl and negative feedback mechanisms controlling Src signaling. Sci. Signal. 4, ra18 (2011).

    PubMed  PubMed Central  Google Scholar 

  3. Eiring, A. M. et al. miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts. Cell 140, 652–665 (2010). In the context of CML disease progression, this paper demonstrated for the first time that microRNAs alter mRNA metabolism not only by base pairing with complementary mRNA targets, but also by competing with mRNAs for interaction with specific RNA-binding proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Packer, L. M. et al. Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell 20, 715–727 (2011). This study identified paradoxical activation of the RAF pathway triggered by treatment of CML with BCR-ABL1 tyrosine kinase inhibitors, and designed effective strategies to induce synthetic lethality.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Med. 2, 561–566 (1996). This paper was the first to describe the selective effects of imatinib on cells containing the BCR-ABL1 fusion protein.

    CAS  PubMed  Google Scholar 

  6. Druker, B. J. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355, 2408–2417 (2006).

    CAS  PubMed  Google Scholar 

  7. Hochhaus, A. et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23, 1054–1061 (2009).

    CAS  PubMed  Google Scholar 

  8. Deininger, M. et al. International Randomized Study of Interferon versus STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) treated with imatinib. Blood 114, 1126 (2009).

    Google Scholar 

  9. Hughes, T. P. et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 349, 1423–1432 (2003).

    CAS  PubMed  Google Scholar 

  10. Gambacorti-Passerini, C. et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J. Natl Cancer Inst. 103, 553–561 (2011).

    CAS  PubMed  Google Scholar 

  11. Kantarjian, H. et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 362, 2260–2270 (2010). This 12-month report describes results of the DASISION trial comparing dasatinib versus imatinib that led to first-line approval of dasatinib for newly diagnosed chronic phase CML.

    CAS  PubMed  Google Scholar 

  12. Kantarjian, H. M. et al. Dasatinib or imatinib in newly diagnosed chronic phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 119, 1123–1129 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Saglio, G. et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 362, 2251–2259 (2010). This is a 12-month report on the ENESTnd trial comparing nilotinib versus imatinib that led to first-line approval of nilotinib for newly diagnosed chronic phase CML.

    CAS  PubMed  Google Scholar 

  14. Jabbour, E. et al. The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood 118, 4541–4546 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Jabbour, E. et al. Predictive factors for outcome and response in patients treated with second-generation tyrosine kinase inhibitors for chronic myeloid leukemia in chronic phase after imatinib failure. Blood 117, 1822–1827 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kantarjian, H. M. et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 12, 841–851 (2011).

    CAS  PubMed  Google Scholar 

  17. Perrotti, D., Jamieson, C., Goldman, J. & Skorski, T. Chronic myeloid leukemia: mechanisms of blastic transformation. J. Clin. Invest. 120, 2254–2264 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Smith, K. M., Yacobi, R. & Van Etten, R. A. Autoinhibition of Bcr-Abl through its SH3 domain. Mol. Cell 12, 27–37 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Nagar, B. et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res. 62, 4236–4243 (2002).

    CAS  PubMed  Google Scholar 

  20. Schindler, T. et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289, 1938–1942 (2000).

    CAS  PubMed  Google Scholar 

  21. Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876–880 (2001). This paper describes the T315I point mutation and BCR-ABL1 gene amplification as mechanisms of clinical resistance to BCR-ABL1 tyrosine kinase inhibitors.

    CAS  PubMed  Google Scholar 

  22. Apperley, J. F. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 8, 1018–1029 (2007).

    CAS  PubMed  Google Scholar 

  23. Soverini, S. et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118, 1208–1215 (2011).

    CAS  PubMed  Google Scholar 

  24. Weisberg, E. et al. Characterization of AMN107, a selective inhibitor of wild-type and mutant Bcr-Abl. Cancer Cell 7, 129–141 (2005).

    CAS  PubMed  Google Scholar 

  25. O'Hare, T. et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 65, 4500–4505 (2005).

    CAS  PubMed  Google Scholar 

  26. Shah, N. P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399–401 (2004). This study that introduced dasatinib underscores the importance of rational design for the production of second-generation targeted therapies.

    CAS  PubMed  Google Scholar 

  27. Burgess, M. R., Skaggs, B. J., Shah, N. P., Lee, F. Y. & Sawyers, C. L. Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proc. Natl Acad. Sci. USA 102, 3395–3400 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Levinson, N. M. & Boxer, S. G. Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the abl tyrosine kinase domain. PLoS ONE 7, e29828 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Redaelli, S. et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J. Clin. Oncol. 27, 469–471 (2009).

    CAS  PubMed  Google Scholar 

  30. Puttini, M. et al. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res. 66, 11314–11322 (2006).

    CAS  PubMed  Google Scholar 

  31. Cortes, J. E. et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 118, 4567–4576 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Khoury, H. J. et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 119, 3403–3412 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Azam, M., Seeliger, M. A., Gray, N. S., Kuriyan, J. & Daley, G. Q. Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nature Struct. Mol. Biol. 15, 1109–1118 (2008).

    CAS  Google Scholar 

  34. O'Hare, T. et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16, 401–412 (2009). This study describes AP24534 (ponatinib), the first pan-BCR-ABL1 tyrosine kinase inhibitor with activity against the T315I gatekeeper mutation.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Huang, W. S. et al. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N−{4-[(4-methylpipera zin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J. Med. Chem. 53, 4701–4719 (2010).

    CAS  PubMed  Google Scholar 

  36. Zhou, T. et al. Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem. Biol. Drug Des. 77, 1–11 (2011).

    CAS  PubMed  Google Scholar 

  37. Chan, W. W. et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell 19, 556–568 (2011). This paper was the preclinical unveiling of DCC-2036, a prototype switch-control tyrosine kinase inhibitor with activity against BCR-ABL1T315I.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Eide, C. A. et al. The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile. Cancer Res. 71, 3189–3195 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Cortes, J. et al. A phase 1 study of DCC-2036, a novel oral inhibitor of BCR-ABL kinase, in patients with Philadelphia chromosome positive (Ph+) leukemias including patients with T315I mutation. Blood 118, 601 (2011).

    Google Scholar 

  40. Weisberg, E. et al. Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRα, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants. Blood 115, 4206–4216 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Corless, C. L., Barnett, C. M. & Heinrich, M. C. Gastrointestinal stromal tumours: origin and molecular oncology. Nature Rev. Cancer 11, 865–878 (2011).

    CAS  Google Scholar 

  42. Nagar, B. et al. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 112, 859–871 (2003).

    CAS  PubMed  Google Scholar 

  43. Hantschel, O. et al. A myristoyl/phosphotyrosine switch regulates c-Abl. Cell 112, 845–857 (2003).

    CAS  PubMed  Google Scholar 

  44. Adrian, F. J. et al. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nature Chem. Biol. 2, 95–102 (2006).

    CAS  Google Scholar 

  45. Zhang, J. et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463, 501–506 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Weisberg, E. et al. Beneficial effects of combining a type II ATP competitive inhibitor with an allosteric competitive inhibitor of BCR-ABL for the treatment of imatinib-sensitive and imatinib-resistant CML. Leukemia 24, 1375–1378 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Jahnke, W. et al. Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay. J. Am. Chem. Soc. 132, 7043–7048 (2010).

    CAS  PubMed  Google Scholar 

  48. Grebien, F. et al. Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis. Cell 147, 306–319 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Dixon, A. S. et al. Disruption of Bcr-Abl coiled coil oligomerization by design. J. Biol. Chem. 286, 27751–27760 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sun, H. et al. Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis. Blood 117, 3151–3162 (2011).

    CAS  PubMed  Google Scholar 

  51. O'Hare, T., Eide, C. A. & Deininger, M. W. New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check. Expert Opin. Investig. Drugs 17, 865–878 (2008).

    CAS  PubMed  Google Scholar 

  52. O'Hare, T., Eide, C. A. & Deininger, M. W. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 110, 2242–2249 (2007).

    CAS  PubMed  Google Scholar 

  53. Kim, W. S. et al. Dynamic change of T315I BCR-ABL kinase domain mutation in Korean chronic myeloid leukaemia patients during treatment with Abl tyrosine kinase inhibitors. Hematol. Oncol. 28, 82–88 (2010).

    CAS  PubMed  Google Scholar 

  54. Stagno, F. et al. Sequential mutations causing resistance to both Imatinib Mesylate and Dasatinib in a chronic myeloid leukaemia patient progressing to lymphoid blast crisis. Leuk. Res. 32, 673–674 (2008).

    CAS  PubMed  Google Scholar 

  55. Khorashad, J. S. et al. In vivo kinetics of kinase domain mutations in CML patients treated with dasatinib after failing imatinib. Blood 111, 2378–2381 (2008).

    CAS  PubMed  Google Scholar 

  56. Jabbour, E. et al. Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood 112, 53–55 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Shah, N. P. et al. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J. Clin. Invest. 117, 2562–2569 (2007). This study reports the appearance of compound drug-resistant BCR-ABL1 mutations following sequential therapy with different BCR-ABL1 tyrosine kinase inhibitors.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Soverini, S. et al. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors. Blood 114, 2168–2171 (2009).

    CAS  PubMed  Google Scholar 

  59. Parker, W. T. et al. Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy. J. Clin. Oncol. 29, 4250–4259 (2011).

    CAS  PubMed  Google Scholar 

  60. Hughes, T. et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J. Clin. Oncol. 27, 4204–4210 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Garg, R. J. et al. The use of nilotinib or dasatinib after failure to two prior tyrosine kinase inhibitors (TKI): long-term follow-up. Blood 114, 4361–4368 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Oda, T. et al. Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J. Biol. Chem. 269, 22925–22928 (1994).

    CAS  PubMed  Google Scholar 

  63. Hochhaus, A. et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16, 2190–2196 (2002).

    CAS  PubMed  Google Scholar 

  64. Burchert, A. et al. Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia 19, 1774–1782 (2005).

    CAS  PubMed  Google Scholar 

  65. Donato, N. J. et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 101, 690–698 (2003).

    CAS  PubMed  Google Scholar 

  66. Esposito, N. et al. SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome-positive cells derived from patients with chronic myeloid leukemia. Blood 118, 3634–3644 (2011).

    CAS  PubMed  Google Scholar 

  67. Gioia, R. et al. Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells. Blood 118, 2211–2221 (2011).

    CAS  PubMed  Google Scholar 

  68. Schmidt, T. et al. Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinib-resistant Bcr-Abl1+ leukemia. Cancer Cell 19, 740–753 (2011).

    CAS  PubMed  Google Scholar 

  69. Gregory, M. A. et al. Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Cancer Cell 18, 74–87 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang, Y. et al. Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. Blood 109, 2147–2155 (2007).

    CAS  PubMed  Google Scholar 

  71. Traer, E. et al. Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors. Leukemia 26, 1140–1143 (2012).

    CAS  PubMed  Google Scholar 

  72. Nair, R. R. et al. Potentiation of nilotinib-mediated cell death in the context of the bone marrow microenvironment requires a promiscuous JAK inhibitor in CML. Leuk. Res. 36, 756–763 (2011).

    PubMed  PubMed Central  Google Scholar 

  73. Weisberg, E. et al. Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia cells. Mol. Cancer Ther. 7, 1121–1129 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Chu, S., Holtz, M., Gupta, M. & Bhatia, R. BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells. Blood 103, 3167–3174 (2004).

    CAS  PubMed  Google Scholar 

  75. Aceves-Luquero, C. I. et al. ERK2, but not ERK1, mediates acquired and “de novo” resistance to imatinib mesylate: implication for CML therapy. PLoS ONE 4, e6124 (2009).

    PubMed  PubMed Central  Google Scholar 

  76. Agarwal, A. et al. An activating KRAS mutation in imatinib-resistant chronic myeloid leukemia. Leukemia 22, 2269–2272 (2008).

    CAS  PubMed  Google Scholar 

  77. Rousselot, P. et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 109, 58–60 (2007).

    CAS  PubMed  Google Scholar 

  78. Jaras, M. et al. Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein. Proc. Natl Acad. Sci. USA 107, 16280–16285 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Herrmann, H. et al. The leukemic stem cell (LSC) in Ph+ CML is a CD34+/CD38-/Lin-cCell that co-expresses dipeptidylpeptidase IV (CD26) and disrupts LSC-niche interactions by degrading the CXCR4 ligand SDF-1α. Blood 118, 961 (2011).

    Google Scholar 

  80. Graham, S. M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99, 319–325 (2002).

    CAS  PubMed  Google Scholar 

  81. Jiang, X. et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia 21, 926–935 (2007).

    CAS  PubMed  Google Scholar 

  82. Copland, M. et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 107, 4532–4539 (2006).

    CAS  PubMed  Google Scholar 

  83. Kumari, A., Brendel, C., Hochhaus, A., Neubauer, A. & Burchert, A. Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib. Blood 119, 530–539 (2012).

    CAS  PubMed  Google Scholar 

  84. Modi, H. et al. Role of BCR/ABL gene-expression levels in determining the phenotype and imatinib sensitivity of transformed human hematopoietic cells. Blood 109, 5411–5421 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Chu, S. et al. Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment. Blood 118, 5565–5572 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Mustjoki, S. et al. Low or undetectable numbers of Philadelphia chromosome-positive leukemic stem cells (Ph+CD34+CD38neg) in chronic myeloid leukemia patients in complete cytogenetic remission after tyrosine kinase inhibitor therapy. Leukemia 24, 219–222 (2010).

    CAS  PubMed  Google Scholar 

  87. Chomel, J. C. et al. Leukemic stem cell persistence in chronic myeloid leukemia patients with sustained undetectable molecular residual disease. Blood 118, 3657–3660 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Corbin, A. S. et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J. Clin. Invest. 121, 396–409 (2011). The authors observe that quiescent human CML stem cells are capable of surviving in vitro despite inhibition of BCR-ABL1 tyrosine kinase activity.

    CAS  PubMed  Google Scholar 

  89. Hamilton, A. et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood 119, 1501–1510 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Takahashi, N., Miura, I., Saitoh, K. & Miura, A. B. Lineage involvement of stem cells bearing the Philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization. Blood 92, 4758–4763 (1998).

    CAS  PubMed  Google Scholar 

  91. Huntly, B. J. et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6, 587–596 (2004).

    CAS  PubMed  Google Scholar 

  92. Jamieson, C. H. et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. 351, 657–667 (2004). This study shows that activation of β-catenin occurs in CML granulocyte–macrophage progenitor cells and is responsible for self-renewal and leukaemic potential in blastic phase CML.

    CAS  PubMed  Google Scholar 

  93. Petzer, A. L. et al. Characterization of primitive subpopulations of normal and leukemic cells present in the blood of patients with newly diagnosed as well as established chronic myeloid leukemia. Blood 88, 2162–2171 (1996).

    CAS  PubMed  Google Scholar 

  94. Koptyra, M. et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 108, 319–327 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Wong, S. et al. Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations. Proc. Natl Acad. Sci. USA 101, 17456–17461 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Corbin, A. S., O'Hare, T., Druker, B. J. & Deininger, M. Suppression of CML progenitor but not CML stem cell growth requires dual inhibition of BCR-ABL and KIT. Blood 112, 190 (2008).

    Google Scholar 

  97. Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nature Rev. Cancer 5, 689–698 (2005).

    CAS  Google Scholar 

  98. Reinhardt, H. C., Jiang, H., Hemann, M. T. & Yaffe, M. B. Exploiting synthetic lethal interactions for targeted cancer therapy. Cell Cycle 8, 3112–3119 (2009).

    CAS  PubMed  Google Scholar 

  99. Ramaraj, P. et al. Effect of mutational inactivation of tyrosine kinase activity on BCR/ABL-induced abnormalities in cell growth and adhesion in human hematopoietic progenitors. Cancer Res. 64, 5322–5331 (2004).

    CAS  PubMed  Google Scholar 

  100. Hu, Y. et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nature Genet. 36, 453–461 (2004).

    CAS  PubMed  Google Scholar 

  101. Hu, Y. et al. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc. Natl Acad. Sci. USA 103, 16870–16875 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Chen, Y., Hu, Y., Zhang, H., Peng, C. & Li, S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genet. 41, 783–792 (2009).

    CAS  PubMed  Google Scholar 

  103. Pellicano, F. et al. BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38- cells, through activation of protein kinase Cβ. Blood 114, 4186–4196 (2009).

    CAS  PubMed  Google Scholar 

  104. Zhang, H., Li, H., Xi, H. S. & Li, S. HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells. Blood 119, 2595–2607 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Ito, K. et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453, 1072–1078 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhang, B. et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 17, 427–442 (2010).

    PubMed  PubMed Central  Google Scholar 

  107. Heaney, N. B. et al. Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells. Blood 115, 2241–2250 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Bellodi, C. et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J. Clin. Invest. 119, 1109–1123 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Li, L. et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 21, 266–281 (2012). This paper reports that SIRT1 is instrumental in the suppression of p53 and that inhibition of SIRT1 and BCR-ABL1 kinase activity led to increased apoptosis in a p53-dependent manner.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Jin, L. et al. CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells. Mol. Cancer Ther. 7, 48–58 (2008).

    CAS  PubMed  Google Scholar 

  111. Vianello, F. et al. Bone marrow mesenchymal stromal cells non-selectively protect chronic myeloid leukemia cells from imatinib-induced apoptosis via the CXCR4/CXCL12 axis. Haematologica 95, 1081–1089 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Weisberg, E. et al. Inhibition of CXCR4 in CML cells disrupts their interaction with the bone marrow microenvironment and sensitizes them to nilotinib. Leukemia 26, 985–990 (2012).

    CAS  PubMed  Google Scholar 

  113. Dillmann, F. et al. Plerixafor inhibits chemotaxis toward SDF-1 and CXCR4-mediated stroma contact in a dose-dependent manner resulting in increased susceptibility of BCR-ABL+ cell to Imatinib and Nilotinib. Leuk. Lymphoma 50, 1676–1686 (2009).

    CAS  PubMed  Google Scholar 

  114. Krause, D. S., Lazarides, K., von Andrian, U. H. & Van Etten, R. A. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nature Med. 12, 1175–1180 (2006).

    CAS  PubMed  Google Scholar 

  115. Reya, T. et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423, 409–414 (2003). This study identified a role for WNT signalling in the development and survival of normal HSCs.

    CAS  PubMed  Google Scholar 

  116. Zhao, C. et al. Loss of β-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12, 528–541 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Heidel, F. H. et al. Genetic and pharmacologic inhibition of β-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem Cell 10, 412–424 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. McWeeney, S. K. et al. A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib. Blood 115, 315–325 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Abrahamsson, A. E. et al. Glycogen synthase kinase 3β missplicing contributes to leukemia stem cell generation. Proc. Natl Acad. Sci. USA 106, 3925–3929 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Coluccia, A. M. et al. Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J. 26, 1456–1466 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Reddiconto, G. et al. Targeting of GSK3β promotes imatinib-mediated apoptosis in quiescent CD34+ chronic myeloid leukemia progenitors, preserving normal stem cells. Blood 119, 2335–2345 (2012).

    CAS  PubMed  Google Scholar 

  122. Schurch, C., Riether, C., Matter, M. S., Tzankov, A. & Ochsenbein, A. F. CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression. J. Clin. Invest. 122, 624–638 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Yao, H., Ashihara, E. & Maekawa, T. Targeting the Wnt/β-catenin signaling pathway in human cancers. Expert Opin. Ther. Targets 15, 873–887 (2011).

    CAS  PubMed  Google Scholar 

  124. Bhardwaj, G. et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nature Immun. 2, 172–180 (2001).

    CAS  PubMed  Google Scholar 

  125. Gao, J. et al. Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell 4, 548–558 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Dierks, C. et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 14, 238–249 (2008).

    CAS  PubMed  Google Scholar 

  127. Zhao, C. et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458, 776–779 (2009). The authors found that activity of the sonic hedgehog signalling pathway is essential for maintenance of normal and leukaemic HSCs.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Jamieson, C. et al. Phase 1 dose-escalation study of PF-04449913, an oral Hedgehog (Hh) inhibitor, in patients with select hematologic malignancies. Blood 118, 424 (2011).

    Google Scholar 

  129. Essafi, A. et al. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene 24, 2317–2329 (2005).

    CAS  PubMed  Google Scholar 

  130. Naka, K. et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463, 676–680 (2010). These data demonstrate that combined inhibition of TFGβ and BCR-ABL1 reduces leukaemia-initiating cells in CML.

    CAS  PubMed  Google Scholar 

  131. Hurtz, C. et al. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J. Exp. Med. 208, 2163–2174 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Duy, C. et al. BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition. Nature 473, 384–388 (2011). This study reports a BCL-6-driven compensatory survival mechanism that is directly and unintentionally triggered by treatment with ABL1 tyrosine kinase inhibitors.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Neviani, P. et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell 8, 355–368 (2005). The paper describes that reactivation of the tumour suppressor phosphatase, PP2A, could provide a therapeutic option for treatment of patients with CML-BP.

    CAS  PubMed  Google Scholar 

  134. Samanta, A. K. et al. Jak2 inhibition deactivates Lyn kinase through the SET-PP2A-SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients. Oncogene 28, 1669–1681 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Lucas, C. M. et al. Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression. Blood 117, 6660–6668 (2011).

    CAS  PubMed  Google Scholar 

  136. Neviani, P. et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J. Clin. Invest. 117, 2408–2421 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Walker, C. et al. PP2A activating drugs (PAD): anti-leukemic and non-toxic activity of two novel and non-immunosuppressive FTY720 derivatives. Blood 116, 2901 (2010).

    Google Scholar 

  138. Neviani, P. et al. BCR-ABL1 kinase activity but not its expression is dispensable for Ph+ quiescent stem cell survival which depends on the PP2A-controlled Jak2 activation and is sensitive to FTY720 treatment. Blood 116, 515 (2010).

    Google Scholar 

  139. Hantschel, O. et al. BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. Nature Chem. Biol. 8, 285–293 (2012). This provocative study presents cellular and enzymatic analyses suggesting that BCR-ABL1 phosphorylates STAT5 directly. One implication of BCR-ABL1-mediated uncoupling of the canonical JAK2–STAT5 pathway is that pharmacological targeting of STAT5 in BCR-ABL1-positive leukaemia must be direct rather than via JAK2.

    CAS  Google Scholar 

  140. Goldman, J. M. et al. Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. J. Clin. Oncol. 28, 1888–1895 (2010).

    PubMed  PubMed Central  Google Scholar 

  141. Burchert, A. et al. Interferon-α, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia. Blood 101, 259–264 (2003).

    CAS  PubMed  Google Scholar 

  142. Preudhomme, C. et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N. Engl. J. Med. 363, 2511–2521 (2010).

    CAS  PubMed  Google Scholar 

  143. Clark, R. E. et al. Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein. Blood 98, 2887–2893 (2001).

    CAS  PubMed  Google Scholar 

  144. Bocchia, M. et al. Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial. Lancet 365, 657–662 (2005).

    CAS  PubMed  Google Scholar 

  145. Cathcart, K. et al. A multivalent bcr-abl fusion peptide vaccination trial in patients with chronic myeloid leukemia. Blood 103, 1037–1042 (2004).

    CAS  PubMed  Google Scholar 

  146. Doulatov, S., Notta, F., Laurenti, E. & Dick, J. E. Hematopoiesis: a human perspective. Cell Stem Cell 10, 120–136 (2012).

    CAS  PubMed  Google Scholar 

  147. Akel, S. et al. Evaluation at single cell level of residual Philadelphia negative hemopoietic stem cells in chronic phase CML patients. Cancer Genet. Cytogenet. 122, 93–100 (2000).

    CAS  PubMed  Google Scholar 

  148. Mullighan, C. G. et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110–114 (2008). These data demonstrated that loss of IKAROS function has a role in the development of Ph+ ALL.

    CAS  PubMed  Google Scholar 

  149. Trageser, D. et al. Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function. J. Exp. Med. 206, 1739–1753 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Fielding, A. K. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 116, 3409–3417 (2010).

    CAS  PubMed  Google Scholar 

  151. Melo, J. V. & Barnes, D. J. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nature Rev. Cancer 7, 441–453 (2007).

    CAS  Google Scholar 

  152. Notta, F. et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 469, 362–367 (2011).

    CAS  PubMed  Google Scholar 

  153. Foa, R. et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 118, 6521–6528 (2011).

    CAS  PubMed  Google Scholar 

  154. Fei, F. et al. Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia. Leukemia 24, 813–820 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Sengupta, A., Ficker, A. M., Dunn, S. K., Madhu, M. & Cancelas, J. A. Bmi1 reprograms CML B-lymphoid progenitors to become B-ALL-initiating cells. Blood 119, 494–502 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Marin, D. et al. European LeukemiaNet criteria for failure or sub-optimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 112, 4437–4444 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Baccarani, M. et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108, 1809–1820 (2006).

    CAS  PubMed  Google Scholar 

  158. Hughes, T. et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 108, 28–37 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Jabbour, E., Cortes, J. E. & Kantarjian, H. M. Suboptimal response to or failure of imatinib treatment for chronic myeloid leukemia: what is the optimal strategy? Mayo Clin. Proc. 84, 161–169 (2009).

    PubMed  PubMed Central  Google Scholar 

  160. Saglio, G. & Fava, C. Practical monitoring of chronic myelogenous leukemia: when to change treatment. J. Natl Compr. Canc. Netw. 10, 121–129 (2012).

    CAS  PubMed  Google Scholar 

  161. Baccarani, M., Castagnetti, F., Gugliotta, G., Palandri, F. & Soverini, S. Response definitions and European Leukemianet management recommendations. Best Pract. Res. Clin. Haematol. 22, 331–341 (2009).

    PubMed  Google Scholar 

  162. Alvarado, Y. et al. Significance of suboptimal response to imatinib, as defined by the European LeukemiaNet, in the long-term outcome of patients with early chronic myeloid leukemia in chronic phase. Cancer 115, 3709–3718 (2009).

    CAS  PubMed  Google Scholar 

  163. Mahon, F. X. et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 11, 1029–1035 (2010). This unusual clinical study asks whether the best responders to imatinib therapy can discontinue taking the drug and maintain deep remissions.

    CAS  PubMed  Google Scholar 

  164. Mahon, F.-X. et al. Discontinuation of imatinib in patients with Chronic Myeloid Leukemia who have maintained complete molecular response: update results of the STIM Study. Blood 118, 603 (2011).

    Google Scholar 

  165. Rousselot, P. et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia (CML) patients (pts) with stable undetectable Bcr-Abl transcripts: results from the French CML group (FILMC). Blood 118, 277 (2011).

    Google Scholar 

  166. Azam, M., Latek, R. R. & Daley, G. Q. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 112, 831–843 (2003).

    CAS  PubMed  Google Scholar 

  167. Irvine, D. A. & Copland, M. Targeting hedgehog in hematologic malignancy. Blood 119, 2196–2204 (2012).

    CAS  PubMed  Google Scholar 

  168. Radich, J. P. et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc. Natl Acad. Sci. USA 103, 2794–2799 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank A. Kohlmann, J. Khorashad and C. A. Eide for assistance with figures and valuable suggestions.

Author information

Authors and Affiliations

  1. Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, 84112, Utah, USA

    Thomas O'Hare, Matthew S. Zabriskie, Anna M. Eiring & Michael W. Deininger

Authors
  1. Thomas O'Hare
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew S. Zabriskie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna M. Eiring
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael W. Deininger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Thomas O'Hare or Michael W. Deininger.

Ethics declarations

Competing interests

M.W.D. serves on advisory boards and as a consultant for Bristol–Myers Squibb, ARIAD, and Novartis and receives research funding from Bristol–Myers Squibb, Celgene, Genzyme and YM BioSciences. T.O'H., M.S.Z. and A.M.E. declare no competing financial interests.

Related links

Glossary

Type II conformation

The inactive or closed conformation of ABL1 and BCR-ABL1 to which imatinib is capable of binding.

Type I conformation

The active or open conformation of ABL1 and BCR-ABL1 to which imatinib is incapable of binding.

'Gatekeeper' mutation

A threonine to isoleucine substitution of amino acid 315 in BCR-ABL1 protein that interferes with the binding of imatinib and other tyrosine kinase inhibitors.

SH2 domain

SRC homology 2 domain. A protein domain capable of binding tyrosine phosphorylated sites.

Aggresomes

Areas within the cell that result from the accumulation of protein for disposal. Aggresomes generally form during times of cellular stress when proteins are misfolded or are partially denatured.

Ubiquitin cycle inhibitors

Compounds that specifically block ubiquitin-cycle regulators such as USP9X.

Hasford score

Similar to the Sokal risk score, this is another prognostic score that can be used at diagnosis to classify patients as low risk, intermediate risk or high risk. This system was developed in 1998 and is based on the outcome of patients treated with interferon-α.

Carboxyfluorescein succinimidyl ester

(CFSE). A fluorescent dye commonly used in proliferation studies owing to halving of CFSE levels within daughter cells following successive divisions.

Long-term culture-initiating cells

An in vitro assay in which mononuclear cells or immunophenotypically selected haematopoietic cells (for example, CD34+ cells) are cultured on bone marrow stromal cells as feeders for up to 6 weeks, sometimes longer. After a defined interval of culture, the haematopoietic cells are harvested and assayed for clonogenic potential (colony growth) in semisolid medium.

P-loop

A conserved loop present in the ABL1 and BCR-ABL1 kinase domains that forms the roof of the active site and coordinates the γ-phosphate group of ATP.

Activation loop

A flexible loop that extends into the active kinase domain and functions as a binding platform for the peptide substrate to be phosphorylated.

Allogeneic stem cell transplant

The transfer of genetically similar but not identical cells from the bone marrow, peripheral blood or cord blood from one individual to another.

Sokal risk score

A prognostic score determined at diagnosis of chronic myeloid leukaemia to classify the patient as either low risk, intermediate risk or high risk. This is the most widely used scoring system, developed in 1984, when busulphan was the standard treatment. The score is based on spleen size, age, blast count and platelet count at diagnosis.

Synthetic lethality

In genetics, an interaction between two non-lethal mutations that, in combination, confer lethality. In chemical genetics, this term can refer to interaction between a drug and a mutation that confers greater drug sensitivity than with the wild type.

Autophagy

A cellular response in which the cell metabolizes its own contents and organelles to maintain energy production. Although such a process can eventually result in cell death, it can also be used to maintain cell survival under conditions of limiting nutrients.

Primary cytogenetic resistance

The inability to achieve a cytogenetic response on first exposure to TKIs.

Cyclosporine A

A calcineurin inhibitor immunosuppressant drug widely used to prevent T cell-mediated allograft rejection in solid organ transplantation and graft versus host disease in haematopoietic stem cell transplantation.

Graft versus leukaemia effect

A beneficial T cell-mediated immune response to host tumour cells by immune cells present in a donor's transplanted tissue.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

O'Hare, T., Zabriskie, M., Eiring, A. et al. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer 12, 513–526 (2012). https://doi.org/10.1038/nrc3317

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3317

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer