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Cited by 62Chronic Myeloid Leukemia TreatmentsChronic Lymphocytic Leukemia ResearchProtein Tyrosine Phosphatases

MYC in chronic myeloid leukemia: induction of aberrant DNA synthesis and association with poor response to imatinib

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Albajar, Marta, Gómez-Casares, M. Teresa, Llorca, Javier, Mauleon, Itsaso, Vaqué, Jose P., Acosta, Juan C., Bermúdez, Arancha, Donato, Nicholas +2 more·2011·Molecular Cancer Research
DOI 10.1158/1541-7786.mcr-10-0356

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Abstract

Untreated chronic myeloid leukemia (CML) progresses from chronic phase to blastic crisis (BC). Increased genomic instability, deregulated proliferation, and loss of differentiation appear associated to BC, but the molecular alterations underlying the progression of CML are poorly characterized. MYC oncogene is frequently deregulated in human cancer, often associated with tumor progression. Genomic instability and induction of aberrant DNA replication are described as effects of MYC. In this report, we studied MYC activities in CML cell lines with conditional MYC expression with and without exposure to imatinib, the front-line drug in CML therapy. In cells with conditional MYC expression, MYC did not rescue the proliferation arrest mediated by imatinib but provoked aberrant DNA synthesis and accumulation of cells with 4C content. We studied MYC mRNA expression in 66 CML patients at different phases of the disease, and we found that MYC expression was higher in CML patients at diagnosis than control bone marrows or in patients responding to imatinib. Further, high MYC levels at diagnosis correlated with a poor response to imatinib. MYC expression did not directly correlate with BCR-ABL levels in patients treated with imatinib. Overall our study suggests that, as in other tumor models, MYC-induced aberrant DNA synthesis in CML cells is consistent with MYC overexpression in untreated CML patients and nonresponding patients and supports a role for MYC in CML progression, possibly through promotion of genomic instability. Mol Cancer Res; 9(5); 564–76. ©2011 AACR.

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  • MYC upregulates glycolysis, DNA-synthesis, and nucleotide metabolism.

    “It is established that MYC upregulates glycolysis, DNA-synthesis, and nucleotide metabolism [80]–[82].”

    From Gene Expression Analysis of Zebrafish Melanocytes, Iridophores, and Retinal Pigmented Epithelium Reveals Indicators of Biological Function and Developmental Origin (2013) · cites this paper as [81]

    The Introduction (page not provided) describes MYC-induced DNA synthesis and mentions enhanced energetic metabolism. The section “Ectopic MYC increased DNA synthesis in K562 cells treated with imatinib” (page not provided) reports increased DNA synthesis after MYC induction. Neither passage establishes the more specific claims that MYC upregulates glycolysis or nucleotide metabolism. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 74

  1. Eilers M, Eisenman RN. Myc's broad reach. Genes Dev 2008;22: 2755-66.
  2. Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. Oncogene 1999;18:3004-16.
  3. Vita M, Henriksson M. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol 2006;16:318-30.
  4. Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nat Rev Cancer 2008;8:976-90.
  5. Wade M, Wahl GM. c-Myc, genome instability, and tumorigenesis: the devil is in the details. Curr Top Microbiol Immunol 2006;302:169-203.
  6. Prochownik EV, Li Y. The ever expanding role for c-Myc in promoting genomic instability. Cell Cycle 2007;6:1024-9.
  7. Lutz W, Leon J, Eilers M. Contributions of Myc to tumorigenesis. Biochim Biophys Acta 2002;1602:61-71.
  8. Karlsson A, Deb-Basu D, Cherry A, Turner S, Ford J, Felsher DW. Defective double-strand DNA break repair and chromosomal trans- locations by MYC overexpression. Proc Natl Acad Sci U S A 2003;100: 9974-9.
  9. Li Q, Dang CV. c-Myc overexpression uncouples DNA replication from mitosis. Mol Cell Biol 1999;19:5339-51.
  10. Kuschak TI, Kuschak BC, Taylor CL, Wright JA, Wiener F, Mai S. c-Myc initiates illegitimate replication of the ribonucleotide reduc- tase R2 gene. Oncogene 2002;21:909-20.
  11. Sheen JH, Dickson RB. Overexpression of c-Myc alters G(1)/S arrest following ionizing radiation. Mol Cell Biol 2002;22:1819-33.
  12. Dominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, et al. Non-transcriptional control of DNA replication by c-Myc. Nature 2007;448:445-51.
  13. Robinson K, Asawachaicharn N, Galloway DA, Grandori C. c-Myc accelerates S-Phase and requires WRN to avoid replication stress. PLoS One 2009;4:e5951.
  14. Herold S, Herkert B, Eilers M. Facilitating replication under stress: an oncogenic function of MYC? Nat Rev Cancer 2009;9:441-4.
  15. Felsher DW, Zetterberg A, Zhu J, Tlsty T, Bishop JM. Overexpression of MYC causes p53-dependent G2 arrest of normal fibroblasts. Proc Natl Acad Sci U S A 2000;97:10544-8.
  16. Cowling VH, Chandriani S, Whitfield ML, Cole MD. A conserved Myc protein domain, MBIV, regulates DNA binding, apoptosis, transforma- tion, and G2 arrest. Mol Cell Biol 2006;26:4226-39.
  17. Gatti G, Maresca G, Natoli M, Florenzano F, Nicolin A, Felsani A, et al. MYC prevents apoptosis and enhances endoreduplication induced by paclitaxel. PLoS One 2009;4:e5442.
  18. Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med 1999;341:164-72.
  19. O'Dwyer ME, Mauro MJ, Druker BJ. Recent advancements in the treatment of chronic myelogenous leukemia. Annu Rev Med 2002;53:369-81.
  20. Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 2005;5:172-83.
  21. Quintas-Cardama A, Cortes J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 2009;113:1619-30.
  22. Clark RE. Facts and uncertainties in monitoring treatment response in chronic myeloid leukaemia. Leuk Res 2009;33:1151-5.
  23. Baccarani M, Pane F, Saglio G. Monitoring treatment of chronic myeloid leukemia. Haematologica 2008;93:161-9.
  24. Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 2007;7:441-53.
  25. Savona M, Talpaz M. Getting to the stem of chronic myeloid leukae- mia. Nat Rev Cancer 2008;8:341-50.
  26. Kavalerchik E, Goff D, Jamieson CH. Chronic myeloid leukemia stem cells. J Clin Oncol 2008;26:2911-5.
  27. Khorashad JS, Wagner S, Greener L, Marin D, Reid A, Milojkovic D, et al. The level of BCR-ABL1 kinase activity before treatment does not identify chronic myeloid leukemia patients who fail to achieve a complete cytogenetic response on imatinib. Haematologica 2009;94: 861-4.
  28. Xie S, Lin H, Sun T, Arlinghaus RB. Jak2 is involved in c-Myc induction by Bcr-Abl. Oncogene 2002;21:7137-46.
  29. Gomez-Casares MT, Vaque JP, Lemes A, Molero T, Delgado MD, Leon J. C-myc expression in cell lines derived from chronic myeloid leukemia. Haematologica 2004;89:241-3.
  30. Samanta AK, Lin H, Sun T, Kantarjian H, Arlinghaus RB. Janus kinase 2: a critical target in chronic myelogenous leukemia. Cancer Res 2006;66:6468-72.
  31. Lugo TG, Witte ON. The BCR-ABL oncogene transforms Rat-1 cells and cooperates with v-myc. Mol Cell Biol 1989;9:1263-70.
  32. Sawyers CL, Callahan W, Witte ON. Dominant negative MYC blocks transformation by ABL oncogenes. Cell 1992;70:901-10.
  33. Afar DE, Goga A, McLaughlin J, Witte ON, Sawyers CL. Differential complementation of Bcr-Abl point mutants with c-Myc. Science 1994;264:424-6.
  34. Handa H, Hegde UP, Kotelnikov VM, et al. Bcl-2 and c-myc expres- sion, cell cycle kinetics and apoptosis during the progression of chronic myelogenous leukemia from diagnosis to blastic phase. Leuk Res 1997;21:479-89.
  35. Beck Z, Bacsi A, Kovacs E, Mundle SD, Dong LM, Burke P, et al. Changes in oncogene expression implicated in evolution of chronic granulocytic leukemia from its chronic phase to acceleration. Leuk Lymphoma 1998;30:293-306.
  36. Notari M, Neviani P, Santhanam R, Blaser BW, Chang JS, Galietta A, et al. A MAPK/HNRPK pathway controls BCR/ABL oncogenic poten- tial by regulating MYC mRNA translation. Blood 2006;107:2507-16.
  37. Blick M, Romero P, Talpaz M, Kurzrock R, Shtalrid M, Andersson B, et al. Molecular characteristics of chronic myelogenous leukemia in blast crisis. Cancer Genet Cytogenet 1987;27:349-56.
  38. Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002;107:76-94.
  39. Brazma D, Grace C, Howard J, Melo JV, Holyoke T, Apperley JF, et al. Genomic profile of chronic myelogenous leukemia: Imbalances asso- ciated with disease progression. Genes Chromosomes Cancer 2007;46:1039-50.
  40. Delgado MD, Lerga A, Canelles M, Gomez-Casares MT, Leon J. Differential regulation of Max and role of c-Myc during erythroid and myelomonocytic differentiation of K562 cells. Oncogene 1995;10: 1659-65.
  41. Littlewood TD, Hancock DC, Danielian PS, Parker MG, Evan GI. A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins. Nucleic Acids Res 1995;23:1686-90.
  42. Lerga A, Richard C, Delgado MD, Cañelles M, Frade P, Cuadrado MA, et al. Apoptosis and mitotic arrest are two independent effects of the protein phosphatases inhibitor okadaic acid in K562 leukemia cells. Biochem Biophys Res Commun 1999;260:256-64.
  43. 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;26:6082-93.
  44. Acosta JC, Ferrandiz N, Bretones G, Torrano V, Blanco R, Richard C, et al. Myc inhibits p27-induced erythroid differentiation of leukemia cells by repressing erythroid master genes without reversing p27- mediated cell cycle arrest. Mol Cell Biol 2008;28:7286-95.
  45. Canelles M, Delgado MD, Hyland KM, et al. Max and inhibitory c-Myc mutants induce erythroid differentiation and resistance to apoptosis in human myeloid leukemia cells. Oncogene 1997;14:1315-27.
  46. Albajar M, Gutierrez P, Richard C, Rosa-Garrido M, G omez-Casares MT, Steegmann JL, et al. PU.1 expression is restored upon treatment of chronic myeloid leukemia patients. Cancer Lett 2008;270: 328-36.
  47. Gabert J, Beillard E, Van Der Velden VH, Bi W, Grimwade D, Pallis- gaard N, et al. Standardization and quality control studies of 'real- time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia-A Europe Against Cancer Program. Leukemia 2003;17:2318-57.
  48. Hurlin PJ, Queva C, Eisenman RN. Mnt, a novel Max-interacting protein is coexpressed with Myc in proliferating cells and mediates repression at Myc binding sites. Genes Dev 1997;11:44-58.
  49. Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and manage- ment recommendations of European LeukemiaNet. J Clin Oncol 2009;27:6041-51.
  50. Neuhaus JM. Statistical methods for longitudinal and clustered designs with binary responses. Stat Methods Med Res 1992;1:249-73.
  51. Munoz-Alonso MJ, Acosta JC, Richard C, Delgado MD, Sedivy J, Leon J. p21Cip1 and p27Kip1 induce distinct cell cycle effects and differentiation programs in myeloid leukemia cells. J Biol Chem 2005;280:18120-9.
  52. Penn LJ, Brooks MW, Laufer EM, Land H. Negative autoregulation of c-myc transcription. Embo J 1990;9:1113-21.
  53. Yin XY, Grove L, Datta NS, Long MW, Prochownik EV. C-myc over- expression and p53 loss cooperate to promote genomic instability. Oncogene 1999;18:1177-84.
  54. Vafa O, Wade M, Kern S, Beeche M, Pandita TK, Hampton GM, et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell 2002;9:1031-44.
  55. Ceballos E, Munoz-Alonso MJ, Berwanger B, Acosta JC, Hern andez R, Krause M, et al. Inhibitory effect of c-Myc on p53-induced apop- tosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes. Oncogene 2005;24:4559-71.
  56. Ceballos E, Delgado MD, Gutierrez P, Richard C, M€ uller D, Eilers M, et al. c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells. Oncogene 2000;19:2194-204.
  57. Gorre ME, Sawyers CL. Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia. Curr Opin Hematol 2002;9:303-7.
  58. Wu J, Meng F, Kong LY, Peng Z, Ying Y, Bornmann WG, et al. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst 2008;100:926-39.
  59. Sears RC. The life cycle of C-myc: from synthesis to degradation. Cell Cycle 2004;3:1133-7.
  60. Lee WM, Schwab M, Westaway D, Varmus HE. Augmented expres- sion of normal c-myc is sufficient for cotransformation of rat embryo cells with a mutant ras gene. Mol Cell Biol 1985;5:3345- 56.
  61. Bazarov AV, Adachi S, Li SF, Mateyak MK, Wei S, Sedivy JM. A modest reduction in c-myc expression has minimal effects on cell growth and apoptosis but dramatically reduces susceptibility to Ras and Raf transformation. Cancer Res 2001;61:1178-86.
  62. Baudino TA, McKay C, Pendeville-Samain H, et al. c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. Genes Dev 2002;16:2530-43.
  63. Murphy DJ, Junttila MR, Pouyet L, Karnezis A, Shchors K, Bui DA, et al. Distinct thresholds govern Myc's biological output in vivo. Cancer Cell 2008;14:447-57.
  64. Wilda M, Busch K, Klose I, Keller T, Woessmann W, Kreuder J, et al. Level of MYC overexpression in pediatric Burkitt's lymphoma is strongly dependent on genomic breakpoint location within the MYC locus. Genes Chromosomes Cancer 2004;41:178-82.
  65. Nowicki MO, Pawlowski P, Fischer T, Hess G, Pawlowski T, Skorski T. Chronic myelogenous leukemia molecular signature. Oncogene 2003;22:3952-63.
  66. McLean LA, Gathmann I, Capdeville R, Polymeropoulos MH, Dress- man M. Pharmacogenomic analysis of cytogenetic response in chronic myeloid leukemia patients treated with imatinib. Clin Cancer Res 2004;10:155-65.
  67. Oehler VG, Yeung KY, Choi YE, Bumgarner RE, Raftery AE, Radich JP. The derivation of diagnostic markers of chronic myeloid leukemia progression from microarray data. Blood 2009;114:3292-8.
  68. Mohty M, Yong AS, Szydlo RM, Apperley JF, Melo JV. The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia. Blood 2007;110:380-3.
  69. Guney I, Sedivy JM. Cellular senescence, epigenetic switches and c-Myc. Cell Cycle 2006;5:2319-23.
  70. Smith DP, Bath ML, Metcalf D, Harris AW, Cory S. MYC levels govern hematopoietic tumor type and latency in transgenic mice. Blood 2006;108:653-61.
  71. Luo H, Li Q, O'Neal J, Kreisel F, Le Beau MM, Tomasson MH. c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations. Blood 2005;106: 2452-61.
  72. Beverly LJ, Varmus HE. MYC-induced myeloid leukemogenesis is accelerated by all six members of the antiapoptotic BCL family. Oncogene 2009;28:1274-9.
  73. Delgado MD, Leon J. Myc roles in hematopoiesis and leukemia. Genes Cancer 2010;1:605-16.
  74. Leon J, Ferrandiz N, Acosta JC, Delgado MD. Inhibition of cell differ- entiation: a critical mechanism for MYC-mediated carcinogenesis? Cell Cycle 2009;8:1148-57.

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Authors
Albajar, M., Gómez-Casares, M. T., Llorca, J., Mauleon, I., Vaqué, J. P., Acosta, J. C., Bermúdez, A., Donato, N., Delgado, M. D., & León, J.
Affiliations
  • Universidad de Cantabria (ES)
  • Authors' Affiliations: 1Departamento de Biología Molecular, Facultad de Medicina, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Universidad de Cantabria-CSIC-SODERCAN; 2Servicio de Hematología, Hospital Universitario Marqués de Valdecilla-IFIMAV; 3Servicio de Hematología, Hospital Universitario Dr. Negrín Las Palmas de Gran Canaria; 4Group of Epidemiology and Computational Biology, University of Cantabria, Santander, and CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; and 5Department of Internal Medicine, Hematology/Oncology Division, University of Michigan Comprehensive Cancer Comprehensive Cancer Center, Ann Arbor, Michigan
ORCID
Venue
Molecular Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2011-05-15
Volume
9
Issue
5
Pages
564-576
ISSN
  • 1541-7786 (ISSN-L)
  • 1557-3125
DOI
10.1158/1541-7786.mcr-10-0356
OpenAlex
W2141077681
Cited by
62
References
2
Citations by year
2026: 1 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 9 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 4 · 2014: 1 · 2013: 5 · 2012: 6
FWCI
2.85
Type
journal article
Language
en
Open access
Locations
  • Molecular Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
MYC oncogene, chronic myeloid leukemia, imatinib resistance, genomic instability, blastic crisis, BCR-ABL, tumor progression
MeSH terms
Imatinib Mesylate, Antineoplastic Agents, Benzamides, DNA Replication, Humans, Piperazines, Protein-Tyrosine Kinases, Pyrimidines, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Fusion Proteins, bcr-abl, Proto-Oncogene Proteins c-myc, Disease Progression, Genomic Instability, Cell Line, Tumor, Protein Kinase Inhibitors

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