Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Annals of Hematology
Published in: Annals of Hematology 2/2015

01-04-2015 | Review Article

Natural course and biology of CML

Authors: Bradley Chereda, Junia V. Melo

Published in: Annals of Hematology | Special Issue 2/2015

Login to get access

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.
Literature
1.
Quintas-Cardama A, Cortes JE (2006) Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc 81(7):973–988PubMed
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):247–254PubMed
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):79–82PubMed
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):587–599PubMed
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):3362–3367PubMed
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):445–454PubMed
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):1981–1987PubMedCentralPubMed
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):2408–2417PubMed
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
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):1029–1035PubMed
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):7519–7527PubMed
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):1208–1215PubMed
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):345–356PubMed
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):1742–1750PubMed
18.
Melo JV (1996) The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood 88(7):2375–2384PubMed
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):946–950PubMed
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):1237–1241PubMed
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):937–941PubMed
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):e3PubMedCentralPubMed
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):1441–1447PubMed
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):3125–3127PubMed
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):992–997PubMed
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):1362–1367PubMedCentralPubMed
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):165–171PubMed
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):1225–1231PubMed
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):1104–1107PubMed
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):546–554PubMed
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):7045–7053PubMed
32.
Hantschel O (2012) Structure, regulation, signaling, and targeting of abl kinases in cancer. Genes Cancer 3(5–6):436–446PubMedCentralPubMed
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):175–185PubMed
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):840–853PubMedCentralPubMed
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):501–506PubMedCentralPubMed
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):824–830PubMed
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):251–253PubMed
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):6649–6653PubMedCentralPubMed
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):2038–2044PubMed
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):9312–9316PubMedCentralPubMed
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):387–399PubMed
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):11823–11827PubMedCentralPubMed
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):85–89PubMed
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):562–565PubMed
45.
Engelman A, Rosenberg N (1990) Temperature-sensitive mutants of Abelson murine leukemia virus deficient in protein tyrosine kinase activity. J Virol 64(9):4242–4251PubMedCentralPubMed
46.
Goldman JM, Melo JV (2003) Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 349(15):1451–1464PubMed
47.
Lin TS, Mahajan S, Frank DA (2000) STAT signaling in the pathogenesis and treatment of leukemias. Oncogene 19(21):2496–2504PubMed
48.
Hennighausen L, Robinson GW (2008) Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes Dev 22(6):711–721PubMedCentralPubMed
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):4720–4728PubMed
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):2167–2175PubMed
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):463–472PubMedCentralPubMed
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):98–110PubMedCentralPubMed
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):3550–3560PubMedCentralPubMed
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):285–293PubMed
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):130–135PubMedCentralPubMed
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):1669–1681PubMedCentralPubMed
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):16296–16300PubMedCentralPubMed
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):839–846PubMed
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):479–492PubMed
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):6151–6161PubMedCentralPubMed
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):5868–5876PubMed
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):3767–3775PubMed
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):2840–2848PubMedCentralPubMed
65.
Salomoni P, Calabretta B (2009) Targeted therapies and autophagy: new insights from chronic myeloid leukemia. Autophagy 5(7):1050–1051PubMed
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):1080–1094PubMed
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):764–773PubMedCentralPubMed
68.
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):715–727PubMedCentralPubMed
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):1159–1167PubMedCentralPubMed
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):968–981PubMedCentralPubMed
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):2401–2411PubMed
73.
Kim LC, Song L, Haura EB (2009) Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol 6(10):587–595PubMed
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):3589–3596PubMed
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):18581–18585PubMed
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):8075–8088PubMed
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):5766–5774PubMedCentralPubMed
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):664–672PubMed
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):2904–2908PubMedCentralPubMed
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):1187–1189PubMed
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):4365–4369PubMedCentralPubMed
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):453–461PubMed
83.
ten Hoeve J, Arlinghaus RB, Guo JQ, Heisterkamp N, Groffen J (1994) Tyrosine phosphorylation of CRKL in Philadelphia + leukemia. Blood 84(6):1731–1736PubMed
84.
Birge RB, Kalodimos C, Inagaki F, Tanaka S (2009) Crk and CrkL adaptor proteins: networks for physiological and pathological signaling. Cell Commun Signal 7:13PubMedCentralPubMed
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):7325–7335PubMedCentralPubMed
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):2520–2526PubMed
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):676–684PubMed
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):299–305PubMed
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):977–984PubMedCentralPubMed
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):1179–1186PubMedCentralPubMed
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):4701–4707PubMed
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):4532–4539PubMed
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):4016–4019PubMed
95.
Kabarowski JH, Witte ON (2000) Consequences of BCR-ABL expression within the hematopoietic stem cell in chronic myeloid leukemia. Stem Cells 18(6):399–408PubMed
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):2056–2064PubMed
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):307–310PubMed
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):245–253PubMed
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):319–325PubMed
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):6187–6197PubMedCentralPubMed
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):396–409PubMedCentralPubMed
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 2965-2966PubMed
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):530–539PubMed
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):528–541PubMedCentralPubMed
105.
Moon RT, Kohn AD, Ferrari GVD, Kaykas A (2004) WNT and [beta]-catenin signalling: diseases and therapies. Nat Rev Genet 5(9):691–701PubMed
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):221–229PubMedCentralPubMed
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):412–424PubMedCentralPubMed
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):160–164PubMed
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):657–667PubMed
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):416–429PubMed
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):1665–1673PubMedCentralPubMed
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):776–779PubMedCentralPubMed
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):4144–4157PubMedCentralPubMed
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):355–368PubMed
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):985–991PubMedCentralPubMed
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):2163–2174PubMedCentralPubMed
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):676–680PubMed
118.
Ellis SL, Nilsson SK (2012) The location and cellular composition of the hemopoietic stem cell niche. Cytotherapy 14(2):135–143PubMed
119.
Ema H, Suda T (2012) Two anatomically distinct niches regulate stem cell activity. Blood 120(11):2174–2181PubMed
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):269–275PubMed
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):1824–1838PubMedCentralPubMed
122.
Perrotti D, Jamieson C, Goldman J, Skorski T (2010) Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest 120(7):2254–2264PubMedCentralPubMed
123.
Skorski T (2012) Genetic mechanisms of chronic myeloid leukemia blastic transformation. Curr Hematol Malig Rep 7(2):87–93PubMed
124.
Johansson B, Fioretos T, Mitelman F (2002) Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 107(2):76–94PubMed
125.
Melo JV, Barnes DJ (2007) Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 7(6):441–453PubMed
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):8912–8919PubMed
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):2371–2378PubMed
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):926–935PubMed
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):1445–1449PubMed
130.
Andrews DF 3rd, Collins SJ (1987) Heterogeneity in expression of the bcr-abl fusion transcript in CML blast crisis. Leukemia 1(10):718–724PubMed
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):994–1003PubMedCentralPubMed
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):387–393PubMed
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):1148–1158PubMed
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):279–286PubMedCentralPubMed
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):1969–1972PubMed
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):629–634PubMedCentralPubMed
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):2084–2090PubMed
138.
Skorski T (2007) Genomic instability: the cause and effect of BCR/ABL tyrosine kinase. Curr Hematol Malig Rep 2(2):69–74PubMed
139.
Skorski T (2008) BCR/ABL, DNA damage and DNA repair: implications for new treatment concepts. Leuk Lymphoma 49(4):610–614PubMed
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):853–863PubMed
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):4080–4089PubMedCentralPubMed
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):652–665PubMedCentralPubMed
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):307–317PubMed
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):22–29PubMed
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):15642–15652PubMed
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):411–421PubMedCentralPubMed
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):3480–3489PubMed
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):1149–1161PubMedCentralPubMed
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):4547–4554PubMed
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):4575–4594PubMedCentralPubMed
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):2239–2256PubMedCentralPubMed
152.
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):507–516PubMed
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):5685–5695PubMedCentralPubMed
155.
Sawyers CL, Callahan W, Witte ON (1992) Dominant negative MYC blocks transformation by ABL oncogenes. Cell 70(6):901–910PubMed
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):552–554PubMed
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):5287–5291PubMedCentralPubMed
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):8905–8911PubMed
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):1499–1507PubMed
160.
Xie S, Lin H, Sun T, Arlinghaus RB (2002) Jak2 is involved in c-Myc induction by Bcr-Abl. Oncogene 21(47):7137–7146PubMed
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):2507–2516PubMedCentralPubMed
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):362–375PubMedCentralPubMed
163.
164.
Pant V, Quintas-Cardama A, Lozano G (2012) The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans. Blood 120(26):5118–5127PubMedCentralPubMed
165.
Guinn BA, Mills KI (1997) p53 mutations, methylation and genomic instability in the progression of chronic myeloid leukaemia. Leuk Lymphoma 26(3–4):211–226PubMed
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):28–35PubMed
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):8371–8374PubMed
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):1463–1472PubMed
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):145–160PubMed
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):7444–7449PubMedCentralPubMed
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):1144–1150PubMed
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):122–132PubMedCentralPubMed
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):67–81PubMed
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):554–564PubMed
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):765–768PubMedCentralPubMed
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):903–908PubMedCentralPubMed
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):71–87PubMedCentralPubMed
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):3034–3044PubMedCentralPubMed
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):1904–1914PubMedCentralPubMed
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):266–281PubMedCentralPubMed
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):589–598PubMedCentralPubMed
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):1041–1046PubMedCentralPubMed
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):1741–1750PubMedCentralPubMed
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):521–528PubMed
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
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):30PubMedCentralPubMed
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):905–912PubMedCentralPubMed
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):1830–1840PubMed
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 10:41PubMedCentralPubMed
190.
Gaj T, Gersbach CA, Barbas CF 3rd (2013) ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 31(7):397–405PubMedCentralPubMed
Metadata
Title
Natural course and biology of CML
Authors
Bradley Chereda
Junia V. Melo
Publication date
01-04-2015
Publisher
Springer Berlin Heidelberg
Published in
Annals of Hematology / Issue Special Issue 2/2015
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-015-2325-z

Other articles of this Special Issue 2/2015

Annals of Hematology 2/2015 Go to the issue

Review Article

Molecular monitoring of chronic myeloid leukemia: principles and interlaboratory standardization

Review Article

Epidemiology of chronic myeloid leukaemia: an update

Review Article

A review of the European LeukemiaNet recommendations for the management of CML

Review Article

The role of hematopoietic stem cell transplantation in chronic myeloid leukemia

Editorial

CML—where do we stand in 2015?

Review Article

Prognostic scores for patients with chronic myeloid leukemia under particular consideration of competing causes of death
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits