Characterization of cancer stem-like cells in a novel STI571-resistant chronic myeloid leukemia cell line
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
To characterize a novel chronic myeloid leukemia (CML) cell line and to further elucidate the mechanisms of resistance to STI571.
A novel K562 cell line (K562/VP16) was achieved after exposure of the K562 cells to VP16. A small subpopulation (K562/VP16 SP) that was capable of excluding Hoechst 33342 in the K562/VP16 cell line was isolated by flow cytometry sorting. The rest of the K562/VP16 cells were classified as non-SP K562/VP16. The mechanisms involved in K562/VP16 SP cells which became resistant to STI571 were studied.
The levels of Bcr-Abl and Abl proteins were similar in the K562 cell line and in non-SP K562/VP16 and K562/VP16 SP cells. The multidrug-resistant gene 1 (MDR1) expression of the 170 kDa P-glycoprotein (P-gp) was detected in K562/VP16 non-SP and K562/VP16 SP cells but not in K562 cells. The expression levels of P-gp in the two K562/VP16 cell lines were similar. Compared with non-SP K562/VP16, the K562/VP16 SP cells were more resistant to STI571. This resistance could hardly be reversed by many multidrug resistance inhibitors. In addition, in vivo study showed that the K562/VP16 SP cells induced tumorigenesis in mice, while the K562/VP16 non-SP cells failed to do so.
A novel K562 cell line, K562/VP16, was generated. A small side population K562/VP16 SP cells, had high resistance to STI571 treatment and more tumorigenic than the K562 cells. It may represent the cancer stem cells of the K562/VP16 cell line.
- Melo JV. The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood, 1996, 88: 2375–2384.
- Raitano AB, Whang YE, Sawyers CL. Signal transduction by wildtype and leukemogenic Abl proteins. Biochim Biophys Acta, 1997, 1333: F201–F216.
- Nieborowska-Skorska M, Wasik MA, Slupianek A, et al. Signal transducer and activator of transcription (STAT)5 activation by BCR/ABL is dependent on intact Src homology (SH)3 and SH2 domains of BCR/ABL and is required for leukemogenesis. J Exp Med, 1999, 189: 1229–1242. CrossRef
- Schindler T, Bornmann W, Pellicena P, et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science, 2000, 289: 1938–1942. CrossRef
- Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med, 2001, 344: 1031–1037. CrossRef
- Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med, 2001, 344: 1038–1042. CrossRef
- Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science, 2001, 293: 876–880. CrossRef
- Mukai M, Che XF, Furukawa T, et al. Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells. Cancer Sci, 2003, 94: 557–563. CrossRef
- Bedi A, Zehnbauer BA, Collector MI, et al. BCR-ABL gene rearrangement and expression of primitive hematopoietic progenitors in chronic myeloid leukemia. Blood, 1993, 81: 2898–2902.
- 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. CrossRef
- Holtz MS, Slovak ML, Zhang F, et al. Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood, 2002, 99: 3792–3800. CrossRef
- Setoguchi T, Taga T, Kondo T. Cancer stem cells persist in many cancer cell lines. Cell Cycle, 2004, 3: 414–415.
- Illmer T, Schaich M, Platzbecker U, et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia, 2004, 18: 401–408. CrossRef
- Illmer T, Schuler US, Thiede C, et al. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res, 2002, 62: 4955–4962.
- Bierhaus A, Illmer T, Kasper M, et al. Advanced glycation end product (AGE)-mediated induction of tissue factor in cultured endothelial cells is dependent on RAGE. Circulation, 1997, 96: 2262–2271.
- Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, 1983, 65: 55–63. CrossRef
- Yu C, Krystal G, Varticovksi L, et al. 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, 2002, 62: 188–199.
- 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.
- Le Coutre P, Tassi E, Varella-Garcia M, et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood, 2000, 95: 1758–1766.
- Mahon FX, Deininger MW, Schultheis B, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood, 2000, 96: 1070–1079.
- Hofmann WK, de Vos S, Elashoff D, et al. Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study. Lancet, 2002, 359: 481–486. CrossRef
- Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer, 2002, 2: 48–58. CrossRef
- Giles FJ, Kantarjian HM, Cortes J, et al. Multidrug resistance protein expression in chronic myeloid leukemia: associations and significance. Cancer, 1999, 86: 805–813. CrossRef
- Mahon FX, Belloc F, Lagarde V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood, 2003, 101: 2368–2373. CrossRef
- Bhatia M, Wang JC, Kapp U, et al. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci USA, 1997, 94: 5320–5325. CrossRef
- Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med, 1997, 3: 730–737. CrossRef
- Blair A, Hogge DE, Ailles LE, et al. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood, 1997, 89: 3104–3112.
- Jordan CT, Upchurch D, Szilvassy SJ, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia, 2000, 14: 1777–1784. CrossRef
- Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA, 2003, 100: 3983–3988. CrossRef
- Characterization of cancer stem-like cells in a novel STI571-resistant chronic myeloid leukemia cell line
The Chinese-German Journal of Clinical Oncology
Volume 6, Issue 4 , pp 383-388
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- cancer stem cell
- side population
- multidrug resistance