Abstract
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder that arises in the hematopoietic stem cell compartment. CML is one of the best-understood malignancies, as it results from a single genetic mutation, the fusion oncogene BCR-ABL, which has been widely studied. Specific tyrosine kinase inhibitors have been developed to target BCR-ABL in CML, but these agents fail to eliminate the CML stem cell population and thus are unlikely to cure CML. This article reviews recent developments in the biology and treatment of CML, specifically focusing on CML stem cells. Significant progress continues to be made in our understanding of CML stem cell biology, which has wider implications within the cancer stem cell field. We are also beginning to see the identification of novel therapies that specifically target the CML stem cell. These are exciting times in the quest to cure CML.
Similar content being viewed by others
References and Recommended Reading
Rowley JD: Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973, 243:290–293.
Savona M, Talpaz M: Getting to the stem of chronic myeloid leukaemia. Nat Rev Cancer 2008, 8:341–350.
Wang JC, Lapidot T, Cashman JD, et al.: High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase. Blood 1998, 91:2406–2414.
Holyoake T, Jiang X, Eaves C, Eaves A: Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 1999, 94:2056–2064.
Copland M, Hamilton A, Elrick LJ, et al.: Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML, but does not eliminate the quiescent fraction. Blood 2006, 107:4532–4539.
Graham SM, Jorgensen HG, Allan E, et al.: Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002, 99:319–325.
Jorgensen HG, Allan EK, Jordanides NE, et al.: Nilotinib exerts equipotent anti-proliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 2007, 109:4016–4019.
Konig H, Holyoake TL, Bhatia R: Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606. Blood 2008, 111:2329–2338.
Jamieson CH, Ailles LE, Dylla SJ, et al.: Granulocytemacrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004, 351:657–667.
Druker BJ, Guilhot F, O’Brien SG, et al.: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006, 355:2408–2417.
Kantarjian H, Giles F, Wunderle L, et al.: Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006, 354:2542–2551.
Talpaz M, Shah NP, Kantarjian H, et al.: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006, 354:2531–2541.
Hughes TP, Kaeda J, Branford S, et al.: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003, 349:1423–1432.
Branford S, Rudzki Z, Grigg A, et al.: BCR-ABL levels continue to decrease up to 42 months after commencement of standard dose imatinib in patients with newly diagnosed chronic phase CML who achieve a molecular response. Blood 2004, 104:82a.
Bhatia R, Holtz M, Niu N, et al.: Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003, 101:4701–4707.
Zhou LL, Zhao Y, Ringrose A, et al.: AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells. J Exp Med 2008, 205:2657–2671.
Jiang X, Zhao Y, Chan WY, et al.: Deregulated expression in Ph+ human leukemias of AHI-1, a gene activated by insertional mutagenesis in mouse models of leukemia. Blood 2004, 103:3897–3904.
Ito K, Bernardi R, Morotti A, et al.: PML targeting eradicates quiescent leukaemia-initiating cells. Nature 2008, 453:1072–1078.
Jin L, Tabe Y, Konoplev S, 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 2008, 7:48–58.
Nie Y, Han YC, Zou YR: CXCR4 is required for the quiescence of primitive hematopoietic cells. J Exp Med 2008, 205:777–783.
Geay JF, Buet D, Zhang Y, et al.: p210BCR-ABL inhibits SDF-1 chemotactic response via alteration of CXCR4 signaling and down-regulation of CXCR4 expression. Cancer Res 2005, 65:2676–2683.
Eiring AM, Neviani P, Santhanam R, et al.: Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis. Blood 2008, 111:816–828.
Perrotti D, Neviani P: From mRNA metabolism to cancer therapy: chronic myelogenous leukemia shows the way. Clin Cancer Res 2007, 13:1638–1642.
Zhao C, Blum J, Chen A, et al.: Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 2007, 12:528–541.
Minami Y, Stuart SA, Ikawa T, et al.: BCR-ABL-transformed GMP as myeloid leukemic stem cells. Proc Natl Acad Sci U S A 2008, 105:17967–17972.
Hu Y, Chen Y, Douglas L, Li S: Beta-catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia 2009, 23:109–116.
Abrahamsson A, Geron I, Gotlib J, et al.: Missplicing of glycogen synthase kinase 3 beta: a potential mechanism of blast crisis chronic myeloid leukemia stem cell generation [abstract]. Blood 2007, 110:238a–239a.
Guzman ML, Li X, Corbett CA, et al.: Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8). Blood 2007, 110:4436–4444.
Kavalerchik E, Gotlib J, Geron I, et al.: Inhibition of chronic myelogenous leukemia stem cells with novel WNT antagonists [abstract]. Blood 2006, 108:74a.
Dierks C, Beigi R, Guo GR, et al.: Expansion of Bcr-Ablpositive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 2008, 14:238–249.
Radich JP, Dai H, Mao M, et al.: Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 2006, 103:2794–2799.
Copland M, Pellicano F, Richmond L, et al.: BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. Blood 2008, 111:2843–2853.
Pellicano F, Copland M, Jorgensen H, et al.: The farnesyltransferase inhibitor BMS-214662 selectively targets primary CML stem cells through activation of caspases [abstract]. Br J Haematol 2008, 141(Suppl 1):121.
Strauss AC, Chu S, Holyoake T, Bhatia R: Effective induction of apoptosis in chronic myeloid leukemia CD34+ cells by the histone deacetylase inhibitor LAQ824 in combination with imatinib [abstract]. Blood 2007, 110:312a.
Burgess A, Ruefli A, Beamish H, et al.: Histone deacetylase inhibitors specifically kill nonproliferating tumour cells. Oncogene 2004, 23:6693–6701.
Neviani P, Santhanam R, Ma Y, et al.: Activation of PP2A by FTY720 inhibits survival and self-renewal of the Ph(+) chronic myelogenous leukemia (CML) CD34+/CD38- stem cell through the simultaneous suppression of BCR/ABL and BCR/ABL-independent signals [abstract]. Blood 2008, 112:77a.
Neviani P, Santhanam R, Trotta R, 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 2005, 8:355–368.
Neering SJ, Bushnell T, Sozer S, et al.: Leukemia stem cells in a genetically defined murine model of blast-crisis CML. Blood 2007, 110:2578–2585.
Komarova NL, Wodarz D: Effect of cellular quiescence on the success of targeted CML therapy. PLoS ONE 2007, 2:e990.
Michor F, Hughes TP, Iwasa Y, et al.: Dynamics of chronic myeloid leukaemia. Nature 2005, 435:1267–1270.
Roeder I, Horn M, Glauche I, et al.: Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications. Nat Med 2006, 12:1181–1184.
Chu S, Xu H, Shah NP, et al.: Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 2005, 105:2093–2098.
Sherbenou DW, Wong MJ, Humayun A, et al.: Mutations of the BCR-ABL-kinase domain occur in a minority of patients with stable complete cytogenetic response to imatinib. Leukemia 2007, 21:489–493.
Jiang X, Saw KM, Eaves A, Eaves C: Instability of BCR-ABL gene in primary and cultured chronic myeloid leukemia stem cells. J Natl Cancer Inst 2007, 99:680–693.
Jiang X, Zhao Y, Smith C, et al.: Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia 2007, 21:926–935.
Jordanides NE, Jorgensen HG, Holyoake TL, Mountford JC: Functional ABCG2 is overexpressed on primary CML CD34+ cells and is inhibited by imatinib mesylate. Blood 2006, 108:1370–1373.
Hiwase DK, Saunders V, Hewett D, et al.: Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications. Clin Cancer Res 2008, 14:3881–3888.
Brendel C, Scharenberg C, Dohse M, et al.: Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells. Leukemia 2007, 21:1267–1275.
Larson RA, Druker BJ, Guilhot F, et al.: Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008, 111:4022–4028.
Picard S, Titier K, Etienne G, et al.: Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007, 109:3496–3499.
Donato NJ, Wu JY, Stapley J, et al.: Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. Cancer Res 2004, 64:672–677
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Copland, M. Chronic myelogenous leukemia stem cells: What’s new?. Curr Hematol Malig Rep 4, 66–73 (2009). https://doi.org/10.1007/s11899-009-0010-9
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11899-009-0010-9