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Natural course and biology of CML

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Abstract

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder arising in the haemopoietic stem cell (HSC) compartment. This disease is characterised by a reciprocal t(9;22) chromosomal translocation, resulting in the formation of the Philadelphia (Ph) chromosome containing the BCR-ABL1 gene. As such, diagnosis and monitoring of disease involves detection of BCR-ABL1. It is the BCR-ABL1 protein, in particular its constitutively active tyrosine kinase activity, that forges the pathogenesis of CML. This aberrant kinase signalling activates downstream targets that reprogram the cell to cause uncontrolled proliferation and results in myeloid hyperplasia and ‘indolent’ symptoms of chronic phase (CP) CML. Without successful intervention, the disease will progress into blast crisis (BC), resembling an acute leukaemia. This advanced disease stage takes on an aggressive phenotype and is almost always fatal. The cell biology of CML is also centred on BCR-ABL1. The presence of BCR-ABL1 can explain virtually all the cellular features of the leukaemia (enhanced cell growth, inhibition of apoptosis, altered cell adhesion, growth factor independence, impaired genomic surveillance and differentiation). This article provides an overview of the clinical and cell biology of CML, and highlights key findings and unanswered questions essential for understanding this disease.

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References

  1. Quintas-Cardama A, Cortes JE (2006) Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc 81(7):973–988

    CAS  PubMed  Google Scholar 

  2. Australian Institute of Health and Welfare (AIHW) (2014). Australian Cancer Incidence and Mortality (ACIM) books: Chronic Myeloid Leukaemia. Canberra: AIHW. www.aihw.gov.au/acim-books. Accessed 25 Febuary 2014

  3. Mendizabal AM, Garcia-Gonzalez P, Levine PH (2013) Regional variations in age at diagnosis and overall survival among patients with chronic myeloid leukemia from low and middle income countries. Cancer Epidemiol 37(3):247–254

    PubMed  Google Scholar 

  4. Corso A, Lazzarino M, Morra E, Merante S, Astori C, Bernasconi P, Boni M, Bernasconi C (1995) Chronic myelogenous leukemia and exposure to ionizing radiation—a retrospective study of 443 patients. Ann Hematol 70(2):79–82

    CAS  PubMed  Google Scholar 

  5. Branford S, Hughes TP, Rudzki Z (1999) Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. Br J Haematol 107(3):587–599

    CAS  PubMed  Google Scholar 

  6. Bose S, Deininger M, Gora-Tybor J, Goldman JM, Melo JV (1998) The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood 92(9):3362–3367

    CAS  PubMed  Google Scholar 

  7. Kantarjian HM, Keating MJ, Talpaz M, Walters RS, Smith TL, Cork A, McCredie KB, Freireich EJ (1987) Chronic myelogenous leukemia in blast crisis. Analysis of 242 patients. Am J Med 83(3):445–454

    CAS  PubMed  Google Scholar 

  8. Melo JV, Barnes DJ (2007) Chronic myeloid leukemia: biology of advanced phase. In: Myeloproliferative Disorders. Springer Berlin Heidelberg, New York, pp 37–59

  9. Ilaria RL, Jr. (2005) Pathobiology of lymphoid and myeloid blast crisis and management issues. Hematol Am Soc Hematol Educ Program 2005:188-194

  10. Kantarjian H, O’Brien S, Jabbour E, Garcia-Manero G, Quintas-Cardama A, Shan J, Rios MB, Ravandi F, Faderl S, Kadia T, Borthakur G, Huang X, Champlin R, Talpaz M, Cortes J (2012) Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood 119(9):1981–1987

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355(23):2408–2417

    CAS  PubMed  Google Scholar 

  12. Deininger M, O’Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes TP, Radich JP, Hatfield AK, Mone M, Filian J, Reynolds J, Gathmann I, Larson RA, Druker BJ (2009) International randomized study of interferon Vs 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. ASH Annu Meet Abstr 22:1126

    Google Scholar 

  13. Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet B, Etienne G, Reiffers J, Rousselot P (2010) 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(11):1029–1035

    CAS  PubMed  Google Scholar 

  14. Milojkovic D, Apperley J (2009) Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res 15(24):7519–7527

    CAS  PubMed  Google Scholar 

  15. Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, Pane F, Muller MC, Ernst T, Rosti G, Porkka K, Baccarani M, Cross NC, Martinelli G (2011) 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(5):1208–1215

    CAS  PubMed  Google Scholar 

  16. Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD (2007) Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 7(5):345–356

    CAS  PubMed  Google Scholar 

  17. Score J, Calasanz MJ, Ottman O, Pane F, Yeh RF, Sobrinho-Simoes MA, Kreil S, Ward D, Hidalgo-Curtis C, Melo JV, Wiemels J, Nadel B, Cross NC, Grand FH (2010) Analysis of genomic breakpoints in p190 and p210 BCR-ABL indicate distinct mechanisms of formation. Leukemia 24(10):1742–1750

    CAS  PubMed  Google Scholar 

  18. Melo JV (1996) The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood 88(7):2375–2384

    CAS  PubMed  Google Scholar 

  19. Elliott SL, Taylor KM, Taylor DL, Rodwell RL, Williams BF, Shuttlewood MM, Wright SJ, Eliadis PE, Bunce IH, Frost TJ et al (1995) Cytogenetic response to alpha-interferon is predicted in early chronic phase chronic myeloid leukemia by M-bcr breakpoint location. Leukemia 9(6):946–950

    CAS  PubMed  Google Scholar 

  20. Mills KI, MacKenzie ED, Birnie GD (1988) The site of the breakpoint within the bcr is a prognostic factor in Philadelphia-positive CML patients. Blood 72(4):1237–1241

    CAS  PubMed  Google Scholar 

  21. Mills KI, Sproul AM, Leibowitz D, Burnett AK (1991) Mapping of breakpoints, and relationship to BCR-ABL RNA expression, in Philadelphia-chromosome-positive chronic myeloid leukaemia patients with a breakpoint around exon 14 (b3) of the BCR gene. Leukemia 5(11):937–941

    CAS  PubMed  Google Scholar 

  22. Balatzenko G, Vundinti BR, Margarita G (2011) Correlation between the type of bcr-abl transcripts and blood cell counts in chronic myeloid leukemia - a possible influence of mdr1 gene expression. Hematol Rep 3(1):e3

    PubMed Central  PubMed  Google Scholar 

  23. Hanfstein B, Lauseker M, Hehlmann R, Saussele S, Erben P, Dietz C, Fabarius A, Proetel U, Schnittger S, Haferlach C, Krause SW, Schubert J, Einsele H, Hanel M, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Pfirrmann M, Hasford J, Hofmann WK, Hochhaus A, Muller MC (2014) Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib. Haematologica 99(9):1441–1447

    CAS  PubMed  Google Scholar 

  24. Inokuchi K, Inoue T, Tojo A, Futaki M, Miyake K, Yamada T, Tanabe Y, Ohki I, Dan K, Ozawa K et al (1991) A possible correlation between the type of bcr-abl hybrid messenger RNA and platelet count in Philadelphia-positive chronic myelogenous leukemia. Blood 78(12):3125–3127

    CAS  PubMed  Google Scholar 

  25. Verschraegen CF, Kantarjian HM, Hirsch-Ginsberg C, Lee MS, O’Brien S, Rios MB, Stass SA, Keating M, Talpaz M (1995) The breakpoint cluster region site in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Clinical, laboratory, and prognostic correlations. Cancer 76(6):992–997

    CAS  PubMed  Google Scholar 

  26. Lucas CM, Harris RJ, Giannoudis A, Davies A, Knight K, Watmough SJ, Wang L, Clark RE (2009) Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript. Haematologica 94(10):1362–1367

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Dowding C, Guo AP, Maisin D, Gordon MY, Goldman JM (1991) The effects of interferon-alpha on the proliferation of CML progenitor cells in vitro are not related to the precise position of the M-BCR breakpoint. Br J Haematol 77(2):165–171

    CAS  PubMed  Google Scholar 

  28. Fioretos T, Nilsson PG, Aman P, Heim S, Kristoffersson U, Malm C, Simonsson B, Turesson I, Mitelman F (1993) Clinical impact of breakpoint position within M-bcr in chronic myeloid leukemia. Leukemia 7(8):1225–1231

    CAS  PubMed  Google Scholar 

  29. Rozman C, Urbano-Ispizua A, Cervantes F, Rozman M, Colomer D, Feliz P, Pujades A, Vives Corrons JL (1995) Analysis of the clinical relevance of the breakpoint location within M-BCR and the type of chimeric mRNA in chronic myelogenous leukemia. Leukemia 9(6):1104–1107

    CAS  PubMed  Google Scholar 

  30. Shepherd P, Suffolk R, Halsey J, Allan N (1995) Analysis of molecular breakpoint and m-RNA transcripts in a prospective randomized trial of interferon in chronic myeloid leukaemia: no correlation with clinical features, cytogenetic response, duration of chronic phase, or survival. Br J Haematol 89(3):546–554

    CAS  PubMed  Google Scholar 

  31. Chu S, Li L, Singh H, Bhatia R (2007) BCR-tyrosine 177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in chronic myelogenous leukemia. Cancer Res 67(14):7045–7053

    CAS  PubMed  Google Scholar 

  32. Hantschel O (2012) Structure, regulation, signaling, and targeting of abl kinases in cancer. Genes Cancer 3(5–6):436–446

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Pendergast AM, Quilliam LA, Cripe LD, Bassing CH, Dai Z, Li N, Batzer A, Rabun KM, Der CJ, Schlessinger J et al (1993) BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell 75(1):175–185

    CAS  PubMed  Google Scholar 

  34. Zhang X, Subrahmanyam R, Wong R, Gross AW, Ren R (2001) The NH(2)-terminal coiled-coil domain and tyrosine 177 play important roles in induction of a myeloproliferative disease in mice by Bcr-Abl. Mol Cell Biol 21(3):840–853

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Zhang J, Adrian FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo G-R, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu G, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS (2010) Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463(7280):501–506

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Daley GQ, Van Etten RA, Baltimore D (1990) Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247(4944):824–830

    CAS  PubMed  Google Scholar 

  37. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J (1990) Acute leukaemia in bcr/abl transgenic mice. Nature 344(6263):251–253

    CAS  PubMed  Google Scholar 

  38. Kelliher MA, McLaughlin J, Witte ON, Rosenberg N (1990) Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc Natl Acad Sci U S A 87(17):6649–6653

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ (1994) Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood 83(8):2038–2044

    CAS  PubMed  Google Scholar 

  40. Daley GQ, Baltimore D (1988) Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. Proc Natl Acad Sci U S A 85(23):9312–9316

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Hariharan IK, Adams JM, Cory S (1988) bcr-abl oncogene renders myeloid cell line factor independent: potential autocrine mechanism in chronic myeloid leukemia. Oncogene Res 3(4):387–399

    CAS  PubMed  Google Scholar 

  42. Ratajczak MZ, Kant JA, Luger SM, Hijiya N, Zhang J, Zon G, Gewirtz AM (1992) In vivo treatment of human leukemia in a scid mouse model with c-myb antisense oligodeoxynucleotides. Proc Natl Acad Sci U S A 89(24):11823–11827

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Skorski T, Szczylik C, Malaguarnera L, Calabretta B (1991) Gene-targeted specific inhibition of chronic myeloid leukemia cell growth by BCR-ABL antisense oligodeoxynucleotides. Folia Histochem Cytobiol 29(3):85–89

    CAS  PubMed  Google Scholar 

  44. Szczylik C, Skorski T, Nicolaides NC, Manzella L, Malaguarnera L, Venturelli D, Gewirtz AM, Calabretta B (1991) Selective inhibition of leukemia cell proliferation by BCR-ABL antisense oligodeoxynucleotides. Science 253(5019):562–565

    CAS  PubMed  Google Scholar 

  45. Engelman A, Rosenberg N (1990) Temperature-sensitive mutants of Abelson murine leukemia virus deficient in protein tyrosine kinase activity. J Virol 64(9):4242–4251

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Goldman JM, Melo JV (2003) Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 349(15):1451–1464

    CAS  PubMed  Google Scholar 

  47. Lin TS, Mahajan S, Frank DA (2000) STAT signaling in the pathogenesis and treatment of leukemias. Oncogene 19(21):2496–2504

    CAS  PubMed  Google Scholar 

  48. Hennighausen L, Robinson GW (2008) Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes Dev 22(6):711–721

    PubMed Central  PubMed  Google Scholar 

  49. Chai SK, Nichols GL, Rothman P (1997) Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients. J Immunol 159(10):4720–4728

    CAS  PubMed  Google Scholar 

  50. Warsch W, Walz C, Sexl V (2013) JAK of all trades: JAK2-STAT5 as novel therapeutic targets in BCR-ABL1+ chronic myeloid leukemia. Blood 122(13):2167–2175

    CAS  PubMed  Google Scholar 

  51. Samanta A, Perazzona B, Chakraborty S, Sun X, Modi H, Bhatia R, Priebe W, Arlinghaus R (2011) Janus kinase 2 regulates Bcr-Abl signaling in chronic myeloid leukemia. Leukemia 25(3):463–472

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Hoelbl A, Schuster C, Kovacic B, Zhu B, Wickre M, Hoelzl MA, Fajmann S, Grebien F, Warsch W, Stengl G, Hennighausen L, Poli V, Beug H, Moriggl R, Sexl V (2010) Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia. EMBO Mol Med 2(3):98–110

    PubMed Central  CAS  PubMed  Google Scholar 

  53. Walz C, Ahmed W, Lazarides K, Betancur M, Patel N, Hennighausen L, Zaleskas VM, Van Etten RA (2012) Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. Blood 119(15):3550–3560

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Hantschel O, Warsch W, Eckelhart E, Kaupe I, Grebien F, Wagner KU, Superti-Furga G, Sexl V (2012) BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. Nat Chem Biol 8(3):285–293

    CAS  PubMed  Google Scholar 

  55. Hansen N, Agerstam H, Wahlestedt M, Landberg N, Askmyr M, Ehinger M, Rissler M, Lilljebjorn H, Johnels P, Ishiko J, Melo JV, Alexander WS, Bryder D, Jaras M, Fioretos T (2013) SOCS2 is dispensable for BCR/ABL1-induced chronic myeloid leukemia-like disease and for normal hematopoietic stem cell function. Leukemia 27(1):130–135

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Schafranek L, Nievergall E, Powell JA, Hiwase DK, Leclercq T, Hughes TP, White DL (2014) Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia. Leukemia 29 (1):76-85

  57. Samanta AK, Chakraborty SN, Wang Y, Kantarjian H, Sun X, Hood J, Perrotti D, Arlinghaus RB (2009) Jak2 inhibition deactivates Lyn kinase through the SET-PP2A-SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients. Oncogene 28(14):1669–1681

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Zhao JJ, Cheng H, Jia S, Wang L, Gjoerup OV, Mikami A, Roberts TM (2006) The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci U S A 103(44):16296–16300

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Sattler M, Salgia R, Okuda K, Uemura N, Durstin MA, Pisick E, Xu G, Li JL, Prasad KV, Griffin JD (1996) The proto-oncogene product p120CBL and the adaptor proteins CRKL and c-CRK link c-ABL, p190BCR/ABL and p210BCR/ABL to the phosphatidylinositol-3′ kinase pathway. Oncogene 12(4):839–846

    CAS  PubMed  Google Scholar 

  60. Sattler M, Mohi MG, Pride YB, Quinnan LR, Malouf NA, Podar K, Gesbert F, Iwasaki H, Li S, Van Etten RA, Gu H, Griffin JD, Neel BG (2002) Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell 1(5):479–492

    CAS  PubMed  Google Scholar 

  61. Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, Wasik MA, Tsichlis PN, Calabretta B (1997) Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J 16(20):6151–6161

    PubMed Central  CAS  PubMed  Google Scholar 

  62. Klejman A, Rushen L, Morrione A, Slupianek A, Skorski T (2002) Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. Oncogene 21(38):5868–5876

    CAS  PubMed  Google Scholar 

  63. Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C (2002) BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 100(10):3767–3775

    CAS  PubMed  Google Scholar 

  64. Sheng Z, Ma L, Sun JE, Zhu LJ, Green MR (2011) BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription. Blood 118(10):2840–2848

    PubMed Central  CAS  PubMed  Google Scholar 

  65. Salomoni P, Calabretta B (2009) Targeted therapies and autophagy: new insights from chronic myeloid leukemia. Autophagy 5(7):1050–1051

    CAS  PubMed  Google Scholar 

  66. Steelman LS, Franklin RA, Abrams SL, Chappell W, Kempf CR, Basecke J, Stivala F, Donia M, Fagone P, Nicoletti F, Libra M, Ruvolo P, Ruvolo V, Evangelisti C, Martelli AM, McCubrey JA (2011) Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia 25(7):1080–1094

    CAS  PubMed  Google Scholar 

  67. Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, Arlinghaus R, Pawson T (1994) Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO J 13(4):764–773

    PubMed Central  CAS  PubMed  Google Scholar 

  68. Baum KJ, Ren R (2008) Effect of Ras inhibition in hematopoiesis and BCR/ABL leukemogenesis. J Hematol Oncol 1:5

    PubMed Central  PubMed  Google Scholar 

  69. Packer LM, Rana S, Hayward R, O’Hare T, Eide CA, Rebocho A, Heidorn S, Zabriskie MS, Niculescu-Duvaz I, Druker BJ, Springer C, Marais R (2011) Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell 20(6):715–727

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Pellicano F, Simara P, Sinclair A, Helgason GV, Copland M, Grant S, Holyoake TL (2011) The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells. Leukemia 25(7):1159–1167

    PubMed Central  CAS  PubMed  Google Scholar 

  71. Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin AS Jr (1998) A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation. Genes Dev 12(7):968–981

    PubMed Central  CAS  PubMed  Google Scholar 

  72. Hsieh MY, Van Etten RA (2014) IKK-dependent activation of NF-kappaB contributes to myeloid and lymphoid leukemogenesis by BCR-ABL1. Blood 123(15):2401–2411

    CAS  PubMed  Google Scholar 

  73. Kim LC, Song L, Haura EB (2009) Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol 6(10):587–595

    PubMed  Google Scholar 

  74. Danhauser-Riedl S, Warmuth M, Druker BJ, Emmerich B, Hallek M (1996) Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells. Cancer Res 56(15):3589–3596

    CAS  PubMed  Google Scholar 

  75. Lionberger JM, Wilson MB, Smithgall TE (2000) Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck. J Biol Chem 275(24):18581–18585

    CAS  PubMed  Google Scholar 

  76. Wilson MB, Schreiner SJ, Choi HJ, Kamens J, Smithgall TE (2002) Selective pyrrolo-pyrimidine inhibitors reveal a necessary role for Src family kinases in Bcr-Abl signal transduction and oncogenesis. Oncogene 21(53):8075–8088

    CAS  PubMed  Google Scholar 

  77. Klejman A, Schreiner SJ, Nieborowska-Skorska M, Slupianek A, Wilson M, Smithgall TE, Skorski T (2002) The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J 21(21):5766–5774

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Warmuth M, Simon N, Mitina O, Mathes R, Fabbro D, Manley PW, Buchdunger E, Forster K, Moarefi I, Hallek M (2003) Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases. Blood 101(2):664–672

    CAS  PubMed  Google Scholar 

  79. Ban K, Gao Y, Amin HM, Howard A, Miller C, Lin Q, Leng X, Munsell M, Bar-Eli M, Arlinghaus RB, Chandra J (2008) BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia. Blood 111(5):2904–2908

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Ptasznik A, Nakata Y, Kalota A, Emerson SG, Gewirtz AM (2004) Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells. Nat Med 10(11):1187–1189

    CAS  PubMed  Google Scholar 

  81. Engelman A, Rosenberg N (1990) bcr/abl and src but not myc and ras replace v-abl in lymphoid transformation. Mol Cell Biol 10(8):4365–4369

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Hu Y, Liu Y, Pelletier S, Buchdunger E, Warmuth M, Fabbro D, Hallek M, Van Etten RA, Li S (2004) Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet 36(5):453–461

    CAS  PubMed  Google Scholar 

  83. ten Hoeve J, Arlinghaus RB, Guo JQ, Heisterkamp N, Groffen J (1994) Tyrosine phosphorylation of CRKL in Philadelphia + leukemia. Blood 84(6):1731–1736

    PubMed  Google Scholar 

  84. Birge RB, Kalodimos C, Inagaki F, Tanaka S (2009) Crk and CrkL adaptor proteins: networks for physiological and pathological signaling. Cell Commun Signal 7:13

    PubMed Central  PubMed  Google Scholar 

  85. Seo J-H, Wood LJ, Agarwal A, O’Hare T, Elsea CR, Griswold IJ, Deininger MWN, Imamoto A, Druker BJ (2010) A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors. Cancer Res 70(18):7325–7335

    PubMed Central  CAS  PubMed  Google Scholar 

  86. White D, Saunders V, Lyons AB, Branford S, Grigg A, To LB, Hughes T (2005) In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML. Blood 106(7):2520–2526

    CAS  PubMed  Google Scholar 

  87. Guo G, Kang Q, Zhu X, Chen Q, Wang X, Chen Y, Ouyang J, Zhang L, Tan H, Chen R, Huang S, Chen JL (2014) A long noncoding RNA critically regulates Bcr-Abl-mediated cellular transformation by acting as a competitive endogenous RNA. Oncogene doi:10.1038/onc.2014.131

  88. Salomoni P, Condorelli F, Sweeney SM, Calabretta B (2000) Versatility of BCR/ABL-expressing leukemic cells in circumventing proapoptotic BAD effects. Blood 96(2):676–684

    CAS  PubMed  Google Scholar 

  89. de Groot RP, Raaijmakers JA, Lammers JW, Koenderman L (2000) STAT5-Dependent CyclinD1 and Bcl-xL expression in Bcr-Abl-transformed cells. Mol Cell Biol Res Commun 3(5):299–305

    PubMed  Google Scholar 

  90. Horita M, Andreu EJ, Benito A, Arbona C, Sanz C, Benet I, Prosper F, Fernandez-Luna JL (2000) Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL. J Exp Med 191(6):977–984

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Neshat MS, Raitano AB, Wang HG, Reed JC, Sawyers CL (2000) The survival function of the Bcr-Abl oncogene is mediated by Bad-dependent and -independent pathways: roles for phosphatidylinositol 3-kinase and Raf. Mol Cell Biol 20(4):1179–1186

    PubMed Central  CAS  PubMed  Google Scholar 

  92. Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL, Arber DA, Slovak ML, Forman SJ (2003) Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101(12):4701–4707

    CAS  PubMed  Google Scholar 

  93. Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N, Barow M, Mountford JC, Holyoake TL (2006) Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 107(11):4532–4539

    CAS  PubMed  Google Scholar 

  94. Jorgensen HG, Allan EK, Jordanides NE, Mountford JC, Holyoake TL (2007) Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 109(9):4016–4019

    CAS  PubMed  Google Scholar 

  95. Kabarowski JH, Witte ON (2000) Consequences of BCR-ABL expression within the hematopoietic stem cell in chronic myeloid leukemia. Stem Cells 18(6):399–408

    CAS  PubMed  Google Scholar 

  96. Holyoake T, Jiang X, Eaves C, Eaves A (1999) Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 94(6):2056–2064

    CAS  PubMed  Google Scholar 

  97. Silvestri F, Banavali S, Yin M, Gopal V, Savignano C, Baccarani M, Preisler HD (1992) CD34-positive cell selection by immunomagnetic beads and chymopapain. Haematologica 77(4):307–310

    CAS  PubMed  Google Scholar 

  98. Eaves C, Udomsakdi C, Cashman J, Barnett M, Eaves A (1993) The biology of normal and neoplastic stem cells in CML. Leuk Lymphoma 11(Suppl 1):245–253

    PubMed  Google Scholar 

  99. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL (2002) Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99(1):319–325

    CAS  PubMed  Google Scholar 

  100. Chakraborty S, Stark JM, Sun CL, Modi H, Chen W, O’Connor TR, Forman SJ, Bhatia S, Bhatia R (2012) Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining. Blood 119(26):6187–6197

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ (2011) Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 121(1):396–409

    PubMed Central  CAS  PubMed  Google Scholar 

  102. Chomel JC, Sorel N, Guilhot J, Guilhot F, Turhan AG (2012) BCR-ABL expression in leukemic progenitors and primitive stem cells of patients with chronic myeloid leukemia. Blood 119(12):2964–2965, author reply 2965-2966

    CAS  PubMed  Google Scholar 

  103. Kumari A, Brendel C, Hochhaus A, Neubauer A, Burchert A (2012) Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib. Blood 119(2):530–539

    CAS  PubMed  Google Scholar 

  104. Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM, Lagoo A, Reya T (2007) Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12(6):528–541

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Moon RT, Kohn AD, Ferrari GVD, Kaykas A (2004) WNT and [beta]-catenin signalling: diseases and therapies. Nat Rev Genet 5(9):691–701

    CAS  PubMed  Google Scholar 

  106. Cobas M, Wilson A, Ernst B, Mancini SJ, MacDonald HR, Kemler R, Radtke F (2004) Beta-catenin is dispensable for hematopoiesis and lymphopoiesis. J Exp Med 199(2):221–229

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Heidel FH, Bullinger L, Feng Z, Wang Z, Neff TA, Stein L, Kalaitzidis D, Lane SW, Armstrong SA (2012) Genetic and pharmacologic inhibition of beta-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem Cell 10(4):412–424

    PubMed Central  CAS  PubMed  Google Scholar 

  108. Koch U, Wilson A, Cobas M, Kemler R, Macdonald HR, Radtke F (2008) Simultaneous loss of beta- and gamma-catenin does not perturb hematopoiesis or lymphopoiesis. Blood 111(1):160–164

    CAS  PubMed  Google Scholar 

  109. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL (2004) Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 351(7):657–667

    CAS  PubMed  Google Scholar 

  110. Briscoe J, Therond PP (2013) The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 14(7):416–429

    PubMed  Google Scholar 

  111. Mar BG, Amakye D, Aifantis I, Buonamici S (2011) The controversial role of the Hedgehog pathway in normal and malignant hematopoiesis. Leukemia 25(11):1665–1673

    PubMed Central  CAS  PubMed  Google Scholar 

  112. Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D, Munchhof M, VanArsdale T, Beachy PA, Reya T (2009) Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458(7239):776–779

    PubMed Central  CAS  PubMed  Google Scholar 

  113. Neviani P, Harb JG, Oaks JJ, Santhanam R, Walker CJ, Ellis JJ, Ferenchak G, Dorrance AM, Paisie CA, Eiring AM, Ma Y, Mao HC, Zhang B, Wunderlich M, May PC, Sun C, Saddoughi SA, Bielawski J, Blum W, Klisovic RB, Solt JA, Byrd JC, Volinia S, Cortes J, Huettner CS, Koschmieder S, Holyoake TL, Devine S, Caligiuri MA, Croce CM, Garzon R, Ogretmen B, Arlinghaus RB, Chen CS, Bittman R, Hokland P, Roy DC, Milojkovic D, Apperley J, Goldman JM, Reid A, Mulloy JC, Bhatia R, Marcucci G, Perrotti D (2013) PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J Clin Invest 123(10):4144–4157

    PubMed Central  CAS  PubMed  Google Scholar 

  114. Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S, Mao H, Chang JS, Galietta A, Uttam A, Roy DC, Valtieri M, Bruner-Klisovic R, Caligiuri MA, Bloomfield CD, Marcucci G, Perrotti D (2005) 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(5):355–368

    CAS  PubMed  Google Scholar 

  115. Atfi A, Abecassis L, Bourgeade MF (2005) Bcr-Abl activates the AKT/Fox O3 signalling pathway to restrict transforming growth factor-beta-mediated cytostatic signals. EMBO Rep 6(10):985–991

    PubMed Central  CAS  PubMed  Google Scholar 

  116. Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM, Herzog S, Ramezani-Rad P, Jumaa H, Muller MC, Hofmann WK, Hochhaus A, Ye BH, Agarwal A, Druker BJ, Shah NP, Melnick AM, Muschen M (2011) BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J Exp Med 208(11):2163–2174

    PubMed Central  CAS  PubMed  Google Scholar 

  117. Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, Nakao S, Motoyama N, Hirao A (2010) TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463(7281):676–680

    CAS  PubMed  Google Scholar 

  118. Ellis SL, Nilsson SK (2012) The location and cellular composition of the hemopoietic stem cell niche. Cytotherapy 14(2):135–143

    PubMed  Google Scholar 

  119. Ema H, Suda T (2012) Two anatomically distinct niches regulate stem cell activity. Blood 120(11):2174–2181

    CAS  PubMed  Google Scholar 

  120. Hazlehurst LA, Argilagos RF, Dalton WS (2007) Beta1 integrin mediated adhesion increases Bim protein degradation and contributes to drug resistance in leukaemia cells. Br J Haematol 136(2):269–275

    CAS  PubMed  Google Scholar 

  121. Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D, Shultz L, Bhatia R (2013) Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-beta-catenin signaling. Blood 121(10):1824–1838

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Perrotti D, Jamieson C, Goldman J, Skorski T (2010) Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest 120(7):2254–2264

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Skorski T (2012) Genetic mechanisms of chronic myeloid leukemia blastic transformation. Curr Hematol Malig Rep 7(2):87–93

    PubMed  Google Scholar 

  124. Johansson B, Fioretos T, Mitelman F (2002) Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 107(2):76–94

    CAS  PubMed  Google Scholar 

  125. Melo JV, Barnes DJ (2007) Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 7(6):441–453

    CAS  PubMed  Google Scholar 

  126. Barnes DJ, Palaiologou D, Panousopoulou E, Schultheis B, Yong AS, Wong A, Pattacini L, Goldman JM, Melo JV (2005) Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Res 65(19):8912–8919

    CAS  PubMed  Google Scholar 

  127. Gaiger A, Henn T, Horth E, Geissler K, Mitterbauer G, Maier-Dobersberger T, Greinix H, Mannhalter C, Haas OA, Lechner K, Lion T (1995) Increase of bcr-abl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression. Blood 86(6):2371–2378

    CAS  PubMed  Google Scholar 

  128. Jiang X, Zhao Y, Smith C, Gasparetto M, Turhan A, Eaves A, Eaves C (2007) Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia 21(5):926–935

    CAS  PubMed  Google Scholar 

  129. Marega M, Piazza RG, Pirola A, Redaelli S, Mogavero A, Iacobucci I, Meneghetti I, Parma M, Pogliani EM, Gambacorti-Passerini C (2010) BCR and BCR-ABL regulation during myeloid differentiation in healthy donors and in chronic phase/blast crisis CML patients. Leukemia 24(8):1445–1449

    CAS  PubMed  Google Scholar 

  130. Andrews DF 3rd, Collins SJ (1987) Heterogeneity in expression of the bcr-abl fusion transcript in CML blast crisis. Leukemia 1(10):718–724

    CAS  PubMed  Google Scholar 

  131. Chang JS, Santhanam R, Trotta R, Neviani P, Eiring AM, Briercheck E, Ronchetti M, Roy DC, Calabretta B, Caligiuri MA, Perrotti D (2007) High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven myeloid differentiation. Blood 110(3):994–1003

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Amos TA, Lewis JL, Grand FH, Gooding RP, Goldman JM, Gordon MY (1995) Apoptosis in chronic myeloid leukaemia: normal responses by progenitor cells to growth factor deprivation, X-irradiation and glucocorticoids. Br J Haematol 91(2):387–393

    CAS  PubMed  Google Scholar 

  133. Bedi A, Barber JP, Bedi GC, el-Deiry WS, Sidransky D, Vala MS, Akhtar AJ, Hilton J, Jones RJ (1995) BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents. Blood 86(3):1148–1158

    CAS  PubMed  Google Scholar 

  134. Dierov J, Sanchez PV, Burke BA, Padilla-Nash H, Putt ME, Ried T, Carroll M (2009) BCR/ABL induces chromosomal instability after genotoxic stress and alters the cell death threshold. Leukemia 23(2):279–286

    PubMed Central  CAS  PubMed  Google Scholar 

  135. Koptyra M, Cramer K, Slupianek A, Richardson C, Skorski T (2008) BCR/ABL promotes accumulation of chromosomal aberrations induced by oxidative and genotoxic stress. Leukemia 22(10):1969–1972

    CAS  PubMed  Google Scholar 

  136. Slupianek A, Falinski R, Znojek P, Stoklosa T, Flis S, Doneddu V, Pytel D, Synowiec E, Blasiak J, Bellacosa A, Skorski T (2013) BCR-ABL1 kinase inhibits uracil DNA glycosylase UNG2 to enhance oxidative DNA damage and stimulate genomic instability. Leukemia 27(3):629–634

    PubMed Central  CAS  PubMed  Google Scholar 

  137. Deutsch E, Dugray A, AbdulKarim B, Marangoni E, Maggiorella L, Vaganay S, M’Kacher R, Rasy SD, Eschwege F, Vainchenker W, Turhan AG, Bourhis J (2001) BCR-ABL down-regulates the DNA repair protein DNA-PKcs. Blood 97(7):2084–2090

    CAS  PubMed  Google Scholar 

  138. Skorski T (2007) Genomic instability: the cause and effect of BCR/ABL tyrosine kinase. Curr Hematol Malig Rep 2(2):69–74

    PubMed  Google Scholar 

  139. Skorski T (2008) BCR/ABL, DNA damage and DNA repair: implications for new treatment concepts. Leuk Lymphoma 49(4):610–614

    CAS  PubMed  Google Scholar 

  140. Zhang P, Iwasaki-Arai J, Iwasaki H, Fenyus ML, Dayaram T, Owens BM, Shigematsu H, Levantini E, Huettner CS, Lekstrom-Himes JA, Akashi K, Tenen DG (2004) Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity 21(6):853–863

    CAS  PubMed  Google Scholar 

  141. Guerzoni C, Bardini M, Mariani SA, Ferrari-Amorotti G, Neviani P, Panno ML, Zhang Y, Martinez R, Perrotti D, Calabretta B (2006) Inducible activation of CEBPB, a gene negatively regulated by BCR/ABL, inhibits proliferation and promotes differentiation of BCR/ABL-expressing cells. Blood 107(10):4080–4089

    PubMed Central  CAS  PubMed  Google Scholar 

  142. Eiring AM, Harb JG, Neviani P, Garton C, Oaks JJ, Spizzo R, Liu S, Schwind S, Santhanam R, Hickey CJ, Becker H, Chandler JC, Andino R, Cortes J, Hokland P, Huettner CS, Bhatia R, Roy DC, Liebhaber SA, Caligiuri MA, Marcucci G, Garzon R, Croce CM, Calin GA, Perrotti D (2010) miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts. Cell 140(5):652–665

    PubMed Central  CAS  PubMed  Google Scholar 

  143. Holtschke T, Lohler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, Lou J, Knobeloch KP, Gabriele L, Waring JF, Bachmann MF, Zinkernagel RM, Morse HC 3rd, Ozato K, Horak I (1996) Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87(2):307–317

    CAS  PubMed  Google Scholar 

  144. Schmidt M, Nagel S, Proba J, Thiede C, Ritter M, Waring JF, Rosenbauer F, Huhn D, Wittig B, Horak I, Neubauer A (1998) Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias. Blood 91(1):22–29

    CAS  PubMed  Google Scholar 

  145. Waight JD, Banik D, Griffiths EA, Nemeth MJ, Abrams SI (2014) Regulation of the interferon regulatory factor-8 (IRF-8) tumor suppressor gene by the signal transducer and activator of transcription 5 (STAT5) transcription factor in chronic myeloid leukemia. J Biol Chem 289(22):15642–15652

    CAS  PubMed  Google Scholar 

  146. Gabriele L, Phung J, Fukumoto J, Segal D, Wang IM, Giannakakou P, Giese NA, Ozato K, Morse HC 3rd (1999) Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein. J Exp Med 190(3):411–421

    PubMed Central  CAS  PubMed  Google Scholar 

  147. Burchert A, Cai D, Hofbauer LC, Samuelsson MK, Slater EP, Duyster J, Ritter M, Hochhaus A, Muller R, Eilers M, Schmidt M, Neubauer A (2004) Interferon consensus sequence binding protein (ICSBP; IRF-8) antagonizes BCR/ABL and down-regulates bcl-2. Blood 103(9):3480–3489

    CAS  PubMed  Google Scholar 

  148. Hao SX, Ren R (2000) Expression of interferon consensus sequence binding protein (ICSBP) is downregulated in Bcr-Abl-induced murine chronic myelogenous leukemia-like disease, and forced coexpression of ICSBP inhibits Bcr-Abl-induced myeloproliferative disorder. Mol Cell Biol 20(4):1149–1161

    PubMed Central  CAS  PubMed  Google Scholar 

  149. Tamura T, Kong HJ, Tunyaplin C, Tsujimura H, Calame K, Ozato K (2003) ICSBP/IRF-8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating myeloid progenitor cells. Blood 102(13):4547–4554

    CAS  PubMed  Google Scholar 

  150. Huang W, Zhou W, Saberwal G, Konieczna I, Horvath E, Katsoulidis E, Platanias LC, Eklund EA (2010) Interferon consensus sequence binding protein (ICSBP) decreases beta-catenin activity in myeloid cells by repressing GAS2 transcription. Mol Cell Biol 30(19):4575–4594

    PubMed Central  CAS  PubMed  Google Scholar 

  151. Scheller M, Schonheit J, Zimmermann K, Leser U, Rosenbauer F, Leutz A (2013) Cross talk between Wnt/beta-catenin and Irf8 in leukemia progression and drug resistance. J Exp Med 210(11):2239–2256

    PubMed Central  CAS  PubMed  Google Scholar 

  152. Dang CV (2012) MYC on the path to cancer. Cell 149(1):22–35

    PubMed Central  CAS  PubMed  Google Scholar 

  153. Preisler HD, Sato H, Yang PM, Wilson M, Kaufman C, Watt R (1988) Assessment of c-myc expression in individual leukemic cells. Leuk Res 12(6):507–516

    CAS  PubMed  Google Scholar 

  154. Cleveland JL, Dean M, Rosenberg N, Wang JY, Rapp UR (1989) Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc: conditional regulation of c-myc transcription by temperature-sensitive v-abl. Mol Cell Biol 9(12):5685–5695

    PubMed Central  CAS  PubMed  Google Scholar 

  155. Sawyers CL, Callahan W, Witte ON (1992) Dominant negative MYC blocks transformation by ABL oncogenes. Cell 70(6):901–910

    CAS  PubMed  Google Scholar 

  156. Bissonnette RP, Echeverri F, Mahboubi A, Green DR (1992) Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature 359(6395):552–554

    CAS  PubMed  Google Scholar 

  157. Sanchez-Garcia I, Grutz G (1995) Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2. Proc Natl Acad Sci U S A 92(12):5287–5291

    PubMed Central  CAS  PubMed  Google Scholar 

  158. Birchenall-Roberts MC, Yoo YD, Bertolette DC 3rd, Lee KH, Turley JM, Bang OS, Ruscetti FW, Kim SJ (1997) The p120-v-Abl protein interacts with E2F-1 and regulates E2F-1 transcriptional activity. J Biol Chem 272(14):8905–8911

    CAS  PubMed  Google Scholar 

  159. Stewart MJ, Litz-Jackson S, Burgess GS, Williamson EA, Leibowitz DS, Boswell HS (1995) Role for E2F1 in p210 BCR-ABL downstream regulation of c-myc transcription initiation. Studies in murine myeloid cells. Leukemia 9(9):1499–1507

    CAS  PubMed  Google Scholar 

  160. Xie S, Lin H, Sun T, Arlinghaus RB (2002) Jak2 is involved in c-Myc induction by Bcr-Abl. Oncogene 21(47):7137–7146

    CAS  PubMed  Google Scholar 

  161. Notari M, Neviani P, Santhanam R, Blaser BW, Chang JS, Galietta A, Willis AE, Roy DC, Caligiuri MA, Marcucci G, Perrotti D (2006) A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation. Blood 107(6):2507–2516

    PubMed Central  CAS  PubMed  Google Scholar 

  162. Reavie L, Buckley SM, Loizou E, Takeishi S, Aranda-Orgilles B, Ndiaye-Lobry D, Abdel-Wahab O, Ibrahim S, Nakayama KI, Aifantis I (2013) Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell 23(3):362–375

    PubMed Central  CAS  PubMed  Google Scholar 

  163. Delgado MD, Leon J (2010) Myc roles in hematopoiesis and leukemia. Genes Cancer 1(6):605–616

    PubMed Central  CAS  PubMed  Google Scholar 

  164. Pant V, Quintas-Cardama A, Lozano G (2012) The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans. Blood 120(26):5118–5127

    PubMed Central  CAS  PubMed  Google Scholar 

  165. Guinn BA, Mills KI (1997) p53 mutations, methylation and genomic instability in the progression of chronic myeloid leukaemia. Leuk Lymphoma 26(3–4):211–226

    CAS  PubMed  Google Scholar 

  166. Stuppia L, Calabrese G, Peila R, Guanciali-Franchi P, Morizio E, Spadano A, Palka G (1997) p53 loss and point mutations are associated with suppression of apoptosis and progression of CML into myeloid blastic crisis. Cancer Genet Cytogenet 98(1):28–35

    CAS  PubMed  Google Scholar 

  167. Sionov RV, Moallem E, Berger M, Kazaz A, Gerlitz O, Ben-Neriah Y, Oren M, Haupt Y (1999) c-Abl neutralizes the inhibitory effect of Mdm2 on p53. J Biol Chem 274(13):8371–8374

    CAS  PubMed  Google Scholar 

  168. Stoklosa T, Slupianek A, Datta M, Nieborowska-Skorska M, Nowicki MO, Koptyra M, Skorski T (2004) BCR/ABL recruits p53 tumor suppressor protein to induce drug resistance. Cell Cycle 3(11):1463–1472

    CAS  PubMed  Google Scholar 

  169. Trotta R, Vignudelli T, Candini O, Intine RV, Pecorari L, Guerzoni C, Santilli G, Byrom MW, Goldoni S, Ford LP, Caligiuri MA, Maraia RJ, Perrotti D, Calabretta B (2003) BCR/ABL activates mdm2 mRNA translation via the La antigen. Cancer Cell 3(2):145–160

    CAS  PubMed  Google Scholar 

  170. Wendel HG, de Stanchina E, Cepero E, Ray S, Emig M, Fridman JS, Veach DR, Bornmann WG, Clarkson B, McCombie WR, Kogan SC, Hochhaus A, Lowe SW (2006) Loss of p53 impedes the antileukemic response to BCR-ABL inhibition. Proc Natl Acad Sci U S A 103(19):7444–7449

    PubMed Central  CAS  PubMed  Google Scholar 

  171. Honda H, Ushijima T, Wakazono K, Oda H, Tanaka Y, Aizawa S, Ishikawa T, Yazaki Y, Hirai H (2000) Acquired loss of p53 induces blastic transformation in p210(bcr/abl)-expressing hematopoietic cells: a transgenic study for blast crisis of human CML. Blood 95(4):1144–1150

    CAS  PubMed  Google Scholar 

  172. Velasco-Hernandez T, Vicente-Duenas C, Sanchez-Garcia I, Martin-Zanca D (2013) p53 restoration kills primitive leukemia cells in vivo and increases survival of leukemic mice. Cell Cycle 12(1):122–132

    PubMed Central  CAS  PubMed  Google Scholar 

  173. Nakamura M, Okano H, Blendy JA, Montell C (1994) Musashi, a neural RNA-binding protein required for Drosophila adult external sensory organ development. Neuron 13(1):67–81

    CAS  PubMed  Google Scholar 

  174. de Andres-Aguayo L, Varas F, Kallin EM, Infante JF, Wurst W, Floss T, Graf T (2011) Musashi 2 is a regulator of the HSC compartment identified by a retroviral insertion screen and knockout mice. Blood 118(3):554–564

    PubMed  Google Scholar 

  175. Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE, Zhao C, Lagoo A, Gerrard G, Foroni L, Goldman J, Goh H, Kim SH, Kim DW, Chuah C, Oehler VG, Radich JP, Jordan CT, Reya T (2010) Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 466(7307):765–768

    PubMed Central  CAS  PubMed  Google Scholar 

  176. Kharas MG, Lengner CJ, Al-Shahrour F, Bullinger L, Ball B, Zaidi S, Morgan K, Tam W, Paktinat M, Okabe R, Gozo M, Einhorn W, Lane SW, Scholl C, Frohling S, Fleming M, Ebert BL, Gilliland DG, Jaenisch R, Daley GQ (2010) Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med 16(8):903–908

    PubMed Central  CAS  PubMed  Google Scholar 

  177. Park SM, Deering RP, Lu Y, Tivnan P, Lianoglou S, Al-Shahrour F, Ebert BL, Hacohen N, Leslie C, Daley GQ, Lengner CJ, Kharas MG (2014) Musashi-2 controls cell fate, lineage bias, and TGF-beta signaling in HSCs. J Exp Med 211(1):71–87

    PubMed Central  CAS  PubMed  Google Scholar 

  178. Walker CJ, Oaks JJ, Santhanam R, Neviani P, Harb JG, Ferenchak G, Ellis JJ, Landesman Y, Eisfeld AK, Gabrail NY, Smith CL, Caligiuri MA, Hokland P, Roy DC, Reid A, Milojkovic D, Goldman JM, Apperley J, Garzon R, Marcucci G, Shacham S, Kauffman MG, Perrotti D (2013) Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph + leukemias. Blood 122(17):3034–3044

    PubMed Central  CAS  PubMed  Google Scholar 

  179. Yuan H, Wang Z, Li L, Zhang H, Modi H, Horne D, Bhatia R, Chen W (2012) Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood 119(8):1904–1914

    PubMed Central  CAS  PubMed  Google Scholar 

  180. Li L, Wang L, Wang Z, Ho Y, McDonald T, Holyoake TL, Chen W, Bhatia R (2012) Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 21(2):266–281

    PubMed Central  CAS  PubMed  Google Scholar 

  181. Wang Z, Yuan H, Roth M, Stark JM, Bhatia R, Chen WY (2013) SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells. Oncogene 32(5):589–598

    PubMed Central  CAS  PubMed  Google Scholar 

  182. Jiang Q, Crews LA, Barrett CL, Chun HJ, Court AC, Isquith JM, Zipeto MA, Goff DJ, Minden M, Sadarangani A, Rusert JM, Dao KH, Morris SR, Goldstein LS, Marra MA, Frazer KA, Jamieson CH (2013) ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proc Natl Acad Sci U S A 110(3):1041–1046

    PubMed Central  CAS  PubMed  Google Scholar 

  183. Steinman RA, Yang Q, Gasparetto M, Robinson LJ, Liu X, Lenzner DE, Hou J, Smith C, Wang Q (2013) Deletion of the RNA-editing enzyme ADAR1 causes regression of established chronic myelogenous leukemia in mice. Int J Cancer 132(8):1741–1750

    PubMed Central  CAS  PubMed  Google Scholar 

  184. Ng KP, Hillmer AM, Chuah CT, Juan WC, Ko TK, Teo AS, Ariyaratne PN, Takahashi N, Sawada K, Fei Y, Soh S, Lee WH, Huang JW, Allen JC Jr, Woo XY, Nagarajan N, Kumar V, Thalamuthu A, Poh WT, Ang AL, Mya HT, How GF, Yang LY, Koh LP, Chowbay B, Chang CT, Nadarajan VS, Chng WJ, Than H, Lim LC, Goh YT, Zhang S, Poh D, Tan P, Seet JE, Ang MK, Chau NM, Ng QS, Tan DS, Soda M, Isobe K, Nothen MM, Wong TY, Shahab A, Ruan X, Cacheux-Rataboul V, Sung WK, Tan EH, Yatabe Y, Mano H, Soo RA, Chin TM, Lim WT, Ruan Y, Ong ST (2012) A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med 18(4):521–528

    CAS  PubMed  Google Scholar 

  185. Kapoor I, Pal P, Lochab S, Kanaujiya JK, Trivedi AK (2012) Proteomics approaches for myeloid leukemia drug discovery. Expert Opin Drug Discovery 7(12):1165–1175

    CAS  Google Scholar 

  186. Halbach S, Rigbolt KT, Wohrle FU, Diedrich B, Gretzmeier C, Brummer T, Dengjel J (2013) Alterations of Gab2 signalling complexes in imatinib and dasatinib treated chronic myeloid leukaemia cells. Cell Commun Signal 11(1):30

    PubMed Central  CAS  PubMed  Google Scholar 

  187. Winter GE, Rix U, Carlson SM, Gleixner KV, Grebien F, Gridling M, Muller AC, Breitwieser FP, Bilban M, Colinge J, Valent P, Bennett KL, White FM, Superti-Furga G (2012) Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML. Nat Chem Biol 8(11):905–912

    PubMed Central  CAS  PubMed  Google Scholar 

  188. Agirre X, Jimenez-Velasco A, San Jose-Eneriz E, Garate L, Bandres E, Cordeu L, Aparicio O, Saez B, Navarro G, Vilas-Zornoza A, Perez-Roger I, Garcia-Foncillas J, Torres A, Heiniger A, Calasanz MJ, Fortes P, Roman-Gomez J, Prosper F (2008) Down-regulation of hsa-miR-10a in chronic myeloid leukemia CD34+ cells increases USF2-mediated cell growth. Mol Cancer Res 6(12):1830–1840

    CAS  PubMed  Google Scholar 

  189. Machova Polakova K, Lopotova T, Klamova H, Burda P, Trneny M, Stopka T, Moravcova J (2011) Expression patterns of microRNAs associated with CML phases and their disease related targets. Mol Cancer 10:41

    PubMed Central  PubMed  Google Scholar 

  190. Gaj T, Gersbach CA, Barbas CF 3rd (2013) ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 31(7):397–405

    PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank Professor Hamish Scott and Associate Professor Sue Branford for their support in writing this review, and Dr David Yeung for helpful discussion. Financial support (salary) was received from the Cancer Council SA.

Conflict of interest

The authors declare that they have no conflict of interest for the writing of this manuscript.

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Authors and Affiliations

  1. Departments of Genetics and Molecular Pathology, and Haematology, Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, 5000, Australia

    Bradley Chereda

  2. Department of Haematology, Centre for Cancer Biology, University of Adelaide, Adelaide, 5000, Australia

    Junia V. Melo

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  1. Bradley Chereda
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  2. Junia V. Melo
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Correspondence to Bradley Chereda.

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Chereda, B., Melo, J.V. Natural course and biology of CML. Ann Hematol 94 (Suppl 2), 107–121 (2015). https://doi.org/10.1007/s00277-015-2325-z

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  • DOI: https://doi.org/10.1007/s00277-015-2325-z

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