Role of anti-apoptotic pathways activated by BCR/ABL in the resistance of chronic myeloid leukemia cells to tyrosine kinase inhibitors

• Autorzy: Danisz K. , Blasiak J.
• Języki publikacji: EN

Abstrakty

EN

Chronic myeloid leukemia (CML) is a hematological stem cell disorder characterized by the excessive proliferation of the myeloid lineage. In its initial chronic phase, the myeloid progenitor cells expand and demonstrate apparently normal differentiation. The disease may then transform into the accelerated phase, usually associated with resistance to therapy, and finally, into acute leukemic progression phase - blast crisis. Abnormal myeloid cells produce progenitors, which have lost their ability to differentiate, but retain the capacity to proliferate. The molecular hallmark of CML is the Philadelphia chromosome, resulting from reciprocal chromosome translocation, t(9;22)(q34;q11), and containing the BCR/ABL fusion gene, producing the BCR/ABL protein with a constitutive tyrosine kinase activity. BCR/ABL-positive cells have faster growth and proliferation over their normal counterparts and are resistant to apoptosis. Introduction of imatinib (IM), a tyrosine kinase inhibitor, revolutionized the therapy of CML, changing it from a fatal disease into a chronic disorder. However, some patients show a primary resistance to IM, others acquire such resistance in the course of therapy. Therefore, a small number of leukemic stem cells retains self-renewal capacity under IM treatment. Because BCR/ABL is involved in many signaling pathways, some of them may be essential for resistance to IM-induced apoptosis. The PI3K/AKT, Ras and JAK/STAT signaling pathways are involved in resistance to apoptosis and can be activated by BCR/ABL. Therefore, they can be candidates for BCR/ABL-dependent pro-survival pathway(s), allowing a fraction of CML cells to withstand treatment with tyrosine kinase inhibitors.

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 2013
• Tom: 60
• Numer: 4
• Opis fizyczny: p.503-514,fig.,ref.

Twórcy

autor

Danisz K.

• Faculty of Biology and Environmental Protection, Department of Molecular Genetics, University of Lodz, Lodz, Poland

autor

Blasiak J.

• Faculty of Biology and Environmental Protection, Department of Molecular Genetics, University of Lodz, Lodz, Poland

Bibliografia

• Ahmed NN, Franke TF, Bellacosa A, Datta K, Gonzalez-Portal ME, Taguchi T, Testa JR, Tsichlis PN (1993) The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential. Oncogene 8: 1957-1963. 
• Al-Ali HK, Heinrich MC, Lange T, Krahl R, Mueller M, Muller C, Niederwieser D, Druker BJ, Deininger MW (2004) High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib. Hematol J 5: 55-60. 
• Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15: 6541-6551. 
• Altman BJ, Jacobs SR, Mason EF, Michalek RD, MacIntyre AN, Coloff JL, Ilkayeva O, Jia W, He YW, Rathmell JC (2011) Autophagy is essential to suppress cell stress and to allow BCR-Abl-mediated leukemogenesis. Oncogene 30: 1855-1867. 
• Amos TA, Lewis JL, Grand FH, Gooding RP, Goldman JM, Gordon MY (1995) Apoptosis in chronic myeloid leukemia: normal responses by progenitor cells to growth factor deprivation, X irradiation and glucocorticoids. Br J Haematol 91: 387-393. 
• Amsberg GK, Schafhausen P (2013) Bosutinib in the management of chronic myelogenous leukemia. Biologics 7: 115-122. 
• Andreeff M, Jiang S, Zhang X, Konopleva M, Estrov Z, Snell VE, Xie Z, Okcu MF, Sanchez-Williams G, Dong J, Estey EH, Champlin RC, Kornblau SM, Reed JC, Zhao S (1999) Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid. Leukemia 13: 1881-1892. 
• Bacher U, Haferlach T, Hiddemann W, Schnittger S, Kern W, Schoch C (2005) Additional clonal abnormalities in Philadelphia-positive ALL and CML demonstrate a different cytogenetic pattern at diagnosis and follow different pathways at progression. Cancer Genet Cytogenet 157: 53-61. 
• Bellodi C, Lidonnici MR, Hamilton A, Helgason GV, Soliera AR, Ronchetti M, Galavotti S, Young KW, Selmi T, Yacobi R, Van Etten RA, Donato N, Hunter A, Dinsdale D, Tirrò E, Vigneri P, Nicotera P, Dyer MJ, Holyoake T, Salomoni P, Calabretta B (2009) Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Invest 119: 1109-1123. 
• Bhatia R, Munthe HA, Verfaillie CM (1999) Role of abnormal integrin-cytoskeletal interactions in impaired 1 integrin function in chronic myelogenous leukemia hematopoietic progenitors. Exp Hematol 27: 1384-1396. 
• Boguski MS, McCormick F (1993) Proteins regulating Ras and its relatives. Nature 366: 643-654. 
• Bokoch GM, Der CJ (1993) Emerging concepts in the Ras superfamily of GTP-binding proteins. Faseb J 7: 750-759. 
• Breedveld P, Beijnen JH, Schellens JH (2006) Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. Trends Pharmacol Sci 27: 17-24. 
• Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ, Lydon NB (1996) Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 56: 100-104. 
• Buchdunger E, O'Reilly T, Wood J (2002) Pharmacology of imatinib (STI571). Eur J Cancer 38 Suppl 5: S28-S36. 
• Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282: 1318-1321. 
• Carlesso N, Frank DA, Griffin JD (1996) Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl. J Exp Med 183: 811-820. 
• Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS, Cantley LC (1990) Purification and characterization of phosphoinositide 3-kinase from rat liver. J Biol Chem 265: 19704-19711. 
• Carroll M, Ohno-Jones S, Tamura S, Buchdunger E, Zimmermann J, Lydon NB, Gilliland DG, Druker BJ (1997) CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 90: 4947-4952. 
• 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: 4720-4728. 
• Chen B, Yi B, Mao R, Liu H, Wang J, Sharma A, Peiper S, Leonard WJ, She JX (2013) Enhanced T cell lymphoma in NOD.Stat5b transgenic mice is caused by hyperactivation of Stat5b in CD8(+) thymocytes. PLoS One 8: e56600. 
• Chin YR, Toker A (2009) Function of Akt/PKB signaling to cell motili­ty, invasion and the tumor stroma in cancer. Cell Signal 21: 470-476. 
• Chopra R, Pu QQ, Elefanty AG (1999) Biology of BCR-ABL. Blood Rev 13: 211-229. 
• Ciarcia R, Damiano S, Montagnaro S, Pagnini U, Ruocco A, Caparrotti G, d'Angelo D, Boffo S, Morales F, Rizzolio F, Florio S, Giordano A (2013) Combined effects of PI3K and SRC kinase inhibitors with imatinib on intracellular calcium levels, autophagy, and apoptosis in CML-PBL cells. Cell Cycle 12: 2839-2848. 
• Cicenas J, Urban P, Vuaroqueaux V, Labuhn M, Kung W, Wight E, Mayhew M, Eppenberger U, Eppenberger-Castori S (2005) Increased level of phosphorylated akt measured by chemiluminescence-linked immunosorbent assay is a predictor of poor prognosis in primary breast cancer overexpressing ErbB-2. Breast Cancer Res 7: R394-R401. 
• Clark SS, Crist WM, Witte ON (1989) Molecular pathogenesis of Ph-positive leukemias. Annu Rev Med 40: 113-22. 
• Cogswell PC, Morgan R, Dunn M, Neubauer A, Nelson P, Poland-Johnston NK, Sandberg AA, Liu E (1989) Mutations of the ras protoncogenes in chronic myelogenous leukemia: a high frequency of ras mutations on bcr/abl rearrangement-negative chronic myelogenous leukemia. Blood 74: 2629-2633. 
• Cortez D, Reuther GW, Pendergast AM (1997) The BCR-ABL tyrosine kinase activates mitotic signaling pathways and stimulates G1-to-S phase transition in hematopoietic cells. Oncogene 15: 2333-2342. 
• Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J (1999) Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide dependent protein kinase-1. Biochem J 337: 575-583. 
• Daley GQ (2003) Towards combination target-directed chemotherapy for chronic myeloid leukemia: role of farnesyl transferase inhibitors. Semin Hematol 40: 11-14. 
• Daley GQ, Van Etten RA, Baltimore D (1991) Blast crisis in a murine model of chronic myelogenous leukemia. Proc Natl Acad Sci USA 88: 11335-11338. 
• 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: 299-305. 
• Deininger M, Buchdunger E, Druker BJ (2005) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105: 2640-2653. 
• Deininger MW, Goldman JM, Lydon N, Melo JV (1997) The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 90: 3691-3698. 
• Deininger MW, Vieira S, Mendiola R, Schultheis B, Goldman JM, Melo JV (2000a) BCR-ABL tyrosine kinase activity regulates the expression of multiple genes implicated in the pathogenesis of chronic myeloid leukemia. Cancer Res 60: 2049-2055. 
• Deininger MW, Goldman JM, Melo JV (2000b) The molecular biology of chronic myeloid leukemia. Blood 96: 3343-3356. 
• Deming PB, Schafer ZT, Tashker JS, Potts MB, Deshmukh M, Kornbluth S (2004) Bcr-Abl-mediated protection from apoptosis downstream of mitochondrial cytochrome C release. Mol Cell Biol 24: 10289-10299. 
• 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: 2084-2090. 
• Downward J, Basu S (2008) YAP and p73: a complex affair. Mol Cell 32: 749-750. 
• Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001a) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344: 1038-1042. 
• Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001b) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344: 1031-1037. 
• Druker BJ, O'Brien SG, Cortes J, Radich J (2002) Chronic myelogenous leukemia. Hematology Am Soc Hematol Educ Program 2002: 111-135. 
• Dubrez L, Eymin B, Sordet O, Droin N, Turhan AG, Solary E (1998) BCR-ABL delays apoptosis upstream of procaspase-3 activation. Blood 91: 2415-2422. 
• Eitel JA, Bijangi-Vishehsaraei K, Saadatzadeh MR, Bhavsar JR, Murphy MP, Pollok KE, Mayo LD (2009) PTEN and p53 are required for hypoxia induced expression of maspin in glioblastoma cells. Cell Cycle 8: 896-901. 
• Engelman JA, Janne PA, Mermel C, Pearlberg J, Mukohara T, Fleet C, Cichowski K, Johnson BE, Cantley LC (2005) ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA 102: 3788-3793. 
• Feinstein E, Cimino G, Gale RP, Alimena G, Berthier R, Kishi K, Goldman J, Zaccaria A, Berrebi A, Canaani E (1991) p53 in chronic myelogenous leukemia in acute phase. Proc Natl Acad Sci USA 88: 6293-6297. 
• Fruman DA, Meyers RE, Cantley LC (1998) Phosphoinositide kinases. Annu Rev Biochem 67: 481-507. 
• Fu Z, Tindall DJ (2008) FOXOs, cancer and regulation of apoptosis. Oncogene 27: 2312-2319. 
• Gaiger A, Henn T, Horth E, Geissler K, Mitterbauer G, Maier-Dobersberger T, Greinix H, Mannhalter C, Haas OA, Lechner K (1995) Increase of bcr-abl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression. Blood 86: 2371-2378. 
• Galbraith PR, Abu-Zahra HT (1972) Granulopoiesis in chronic granulocytic leukaemia. Br J Haematol 22: 135-143. 
• Galle PR (2008) Sorafenib in advanced hepatocellular carcinoma - we have won a battle but not the war. J Hepatol 49: 871-873. 
• Gambacorti-Passerini C, le Coutre P, Mologni L, Fanelli M, Bertazzoli C, Marchesi E, Di Nicola M, Biondi A, Corneo GM, Belotti D, Pogliani E, Lydon NB (1997) Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+leukemic cells and induces apoptosis. Blood Cells Mol Dis 23: 380-394. 
• Gishizky ML, Johnson-White J, Witte ON (1993) Efficient transplantation of BCR-ABL-induced chronic myelogenous leukemia-like syndrome in mice. Proc Natl Acad Sci USA 90: 3755-3759. 
• Goetz AW, van der Kuip H, Maya R, Oren M, Aulitzky WE (2001) Requirement for Mdm2 in the survival effects of Bcr-Abl and interleukin 3 in hematopoietic cells. Cancer Res 61: 7635-7641. 
• Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293: 876-880. 
• Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G (1984) Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36: 93-99. 
• Grossmann V, Kohlmann A, Zenger M, Schindela S, Eder C, Weissmann S, Schnittger S, Kern W, Muller MC, Hochhaus A, Haferlach T, Haferlach C (2011) A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases. Leukemia 25: 557-560. 
• Guilhot F (2004) Sustained durability of response plus high rates of cytogenetic responses results in long-term benefit for newly diagnosed chronic-phase chronic myeloid leukemia (Ph+CML-CP) treated with imatinib (IM) therapy: update from the IRIS study. Blood 104: 10a
• Harrington LS, Findlay GM, Lamb RF (2005) Restraining PI3K: mTOR signalling goes back to the membrane. Trends Biochem Sci 30: 35-42. 
• Harrison-Findik D, Susa M, Varticovski L (1995) Association of phosphatidylinositol 3-kinase with SHC in chronic myelogeneous leukemia cells. Oncogene 10: 1385-1391. 
• Hawkins PT, Welch H, McGregor A, Eguinoa A, Gobert S, Krugmann S, Anderson K, Stokoe D, Stephens L (1997) Signalling via phosphoinositide 3OH kinases. Biochem Soc Trans 25: 1147-1151. 
• Helgason GV, Karvela M, Holyoake TL (2011) Kill one bird with two stones: potential efficacy of BCR-ABL and autophagy inhibition in CML. Blood 118: 2035-2043. 
• Hickey FB, Cotter TG (2006) BCR-ABL regulates phosphatidylinositol 3-kinase-p110 gamma transcription and activation and is required for proliferation and drug resistance. J Biol Chem 281: 2441-2450. 
• Higa A, Chevet E (2012) Redox signaling loops in the unfolded protein response. Cell Signal 24: 1548-1555. 
• Hirano I, Nakamura S, Yokota D, Ono T, Shigeno K, Fujisawa S, Shinjo K, Ohnishi K (2009) Depletion of Pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 by Bcr-Abl promotes chronic myelogenous leukemia cell proliferation through continuous phosphorylation of Akt isoforms. J Biol Chem 284: 22155-22165. 
• Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U, Gschaidmeier H, Druker BJ, Hehlmann R (2002) Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16: 2190-2196. 
• Hochhaus A, La Rosee P (2004) Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 18: 1321-1331. 
• 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: 977-984. 
• Jain SK, Langdon WY, Varticovski L (1997) Tyrosine phosphorylation of p120cbl in BCR/abl transformed hematopoietic cells mediates enhanced association with phosphatidylinositol 3-kinase. Oncogene 14: 2217-2228. 
• Jiang Y, Zhao RC, Verfaillie CM (2000) Abnormal integrin-mediated regulation of chronic myelogenous leukemia CD34 cell proliferation: BCR/ABL up-regulates the cyclin-dependent kinase inhibitor, p27Kip, which is relocated to the cell cytoplasm and incapable of regulating cdk2 activity. Proc Natl Acad Sci USA 97: 10538-10543. 
• Kaymaz BT, Selvi N, Gündüz C, Aktan C, Dalmızrak A, Saydam G, Kosova B (2013) Repression of STAT3, STAT5A, and STAT5B expressions in chronic myelogenous leukemia cell line K-562 with unmodified or chemically modified siRNAs and induction of apoptosis. Ann Hematol 92: 151-162. 
• Keating A (1987) Ph positive CML cell lines. Baillieres Clin Haematol 1: 1021-1029. 
• Kharas MG, Fruman DA (2005) ABL oncogenes and phosphoinositide 3-kinase: mechanism of activation and downstream effectors. Cancer Res 65: 2047-2053. 
• Kim TD, Turkmen S, Schwarz M, Koca G, Nogai H, Bommer C, Dorken B, Daniel P, le Coutre P (2010) Impact of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia. Haematologica 95: 582-588. 
• Klein PJ, Schmidt CM, Wiesenauer CA, Choi JN, Gage EA, Yip-Schneider MT, Wiebke EA, Wang Y, Omer C, Sebolt-Leopold JS (2006) The effects of a novel MEK inhibitor PD184161 on MEK-ERK signaling and growth in human liver cancer. Neoplasia 8: 1-8. 
• 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: 5766-5774. 
• Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I, Nieborowska-Skorska M, Blasiak J, Skorski T (2006) BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 108: 319-327. 
• Koury MJ (1992) Programmed cell death (apoptosis) in hematopoiesis. Exp Hematol 20: 391-394. 
• Krempler A, Qi Y, Triplett AA, Zhu J, Rui H, Wagner KU (2004) Generation of a conditional knockout allele for the Janus kinase 2 (Jak2) gene in mice. Genesis 40: 52-57. 
• Kriss CL, Pinilla-Ibarz JA, Mailloux AW, Powers JJ, Tang CH, Kang CW, Zanesi N, Epling-Burnette PK, Sotomayor EM, Croce CM, Del Valle JR, Hu CC (2012) Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice. Blood 120: 1027-1038. 
• Kusio-Kobialka M, Podszywalow-Bartnicka P, Peidis P, Glodkowska-Mrowka E, Wolanin K, Leszak G, Seferynska I, Stoklosa T, Koromilas AE, Piwocka K (2012) The PERK-eIF2α phosphorylation arm is a pro-survival pathway of BCR-ABL signaling and confers resistance to imatinib treatment in chronic myeloid leukemia cells. Cell Cycle 11: 4069-4078. 
• Lahaye T, Riehm B, Berger U, Paschka P, Muller MC, Kreil S, Merx K, Schwindel U, Schoch C, Hehlmann R, Hochhaus A (2005) Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up. Cancer 103: 1659-1669. 
• Laneuville P, Sun G, Timm M, Vekemans M (1992) Clonal evolution in a myeloid cell line transformed to interleukin-3 independent growth by retroviral transduction and expression of p210bcr/abl. Blood 80: 1788-1797. 
• Li J, Favata M, Kelley JA, Caulder E, Thomas B, Wen X, Sparks RB, Arvanitis A, Rogers JD, Combs AP, Vaddi K, Solomon KA, Scherle PA, Newton R, Fridman JS (2010) INCB16562, a JAK1/2 selective inhibitor, is efficacious against multiple myeloma cells and reverses the protective effects of cytokine and stromal cell support. Neoplasia 12: 28-38. 
• Li S, Ilaria RL Jr, Million RP, Daley GQ, Van Etten RA (1999) The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. J Exp Med 189: 1399-1412. 
• Liu KD, Gaffen SL, Goldsmith MA (1998) JAK/STAT signaling by cytokine receptors. Curr Opin Immunol 10: 271-278. 
• Lugo TG, Pendergast AM, Muller AJ, Witte ON (1990) Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247: 1079-1082. 
• Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, Melo JV (2000) Selection and characterization of BCRABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 96: 1070-1079. 
• Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR (2006) Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21: 749-760. 
• McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Basecke J, Libra M, Stivala F, Milella M, Tafuri A, Lunghi P, Bonati A, Martelli AM (2008) Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/AKT/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia 22: 708-722. 
• Medema RH, Kops GJ, Bos JL, Burgering BM (2000) AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404: 782-787. 
• Millward TA, Zolnierowicz S, Hemmings BA (1999) Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 24: 186-191. 
• Mitelman F (1993) The cytogenetic scenario of chronic myeloid leukemia. Leuk Lymphoma 11: 11-15. 
• Naughton R, Quiney C, Turner SD, Cotter TG (2009) Bcr-Abl-mediated redox regulation of the PI3K/AKT pathway. Leukemia 23: 1432-1440. 
• 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: 1179-1186. 
• Nishii K, Kabarowski JH, Gibbons DL, Griffiths SD, Titley I, Wiedemann LM, Greaves MF (1996) ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block. Oncogene 13: 2225-2234. 
• Nowak D, Ogawa S, Muschen M, Kato M, Kawamata N, Meixel A, Nowak V, Kim HS, Kang S, Paquette R, Chang MS, Thoennissen NH, Mossner M, Hofmann WK, Kohlmann A, Weiss T, Haferlach T, Haferlach C, Koeffler HP (2010) SNP array analysis of tyrosine kinase inhibitor (TKI) resistant chronic myeloid leukemia (CML) identifies heterogeneous secondary genomic alterations. Blood 115: 1049-1053. 
• Nowell P, Hungerford D (1960) A minute chromosome in human chronic granulocytic leukemia. Science 132: 1497.
• Nowell PC, Hungerford DA (1961) Chromosome studies in human leukemia. II. Chronic granulocytic leukemia. J Natl Cancer Inst 27: 1013-1035. 
• O'Dwyer M (2002) Multifaceted approach to the treatment of Bcr-Abl-positive leukemias. The Oncologist 7: 30-38. 
• Oda T, Tamura S, Matsuguchi T, Griffin JD, Druker BJ (1995) The SH2 domain of ABL is not required for factor-independent growth induced by BCR-ABL in a murine myeloid cell line. Leukemia 9: 295-301. 
• O'Loghlen A, Perez-Morgado MI, Salinas M, Martin ME (2003) Reversible inhibition of the protein phosphatase 1 by hydrogen peroxide. Potential regulation of eIF2 alpha phosphorylation in differentiated PC12 cells. Arch Biochem Biophys 417: 194-202. 
• Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401: 82-85. 
• Parcellier A, Tintignac LA, Zhuravleva E, Hemmings BA (2008) PKB and the mitochondria: AKTing on apoptosis. Cell Signal 20: 21-30. 
• Pelicci G, Lanfrancone L, Salcini AE, Romano A, Mele S, Grazia Borrello M, Segatto O, Di Fiore PP, Pelicci PG (1995) Constitutive phosphorylation of Shc proteins in human tumors. Oncogene 11: 899-907. 
• 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: 1159-1167. 
• Peng B, Lloyd P, Schran H (2005) Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 44: 879-894. 
• Piwocka K, Vejda S, Cotter TG, O'Sullivan GC, McKenna SL (2006) Bcr-Abl reduces endoplasmic reticulum releasable calcium levels by a Bcl-2-independent mechanism and inhibits calcium-dependent apoptotic signaling. Blood 107: 4003-4010. 
• Polak R, Buitenhuis M (2012) The PI3K/PKB signaling module as key regulator of hematopoiesis: implications for therapeutic strategies in leukemia. Blood 119: 911-923. 
• Press RD, Kamel-Reid S, Ang D (2013) BCR-ABL1 RT-qPCR for monitoring the molecular response to tyrosine kinase inhibitors in chronic myeloid leukemia. J Mol Diagn 15: 565-576. 
• 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 signaling pathway. EMBO J 13: 764-773. 
• Rao RK, Clayton LW (2002) Regulation of protein phosphatase 2A by hydrogen peroxide and glutathionylation. Biochem Biophys Res Commun 293: 610-616. 
• Regimbeau JM, Colombat M, Mognol P, Durand F, Abdalla E, Degott C, Degos F, Farges O, Belghiti J (2004) Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl 10: S69-73. 
• Ren R (2005) Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5: 172-183. 
• Ren SY, Bolton E, Mohi MG, Morrione A, Neel BG, Skorski T (2005a) Phosphatidylinositol 3-kinase p85{alpha} subunit-dependent interaction with BCR/ABL-related fusion tyrosine kinases: molecular mechanisms and biological consequences. Mol Cell Biol 25: 8001-8008. 
• Ren SY, Xue F, Feng J, Skorski T (2005b) Intrinsic regulation of the interactions between the SH3 domain of p85 subunit of phosphatidylinositol-3 kinase and the protein network of BCR/ABL oncogenic tyrosine kinase. Exp Hematol 33: 1222-1228. 
• Riordan FA, Bravery CA, Mengubas K, Ray N, Borthwick NJ, Akbar AN, Hart SM, Hoffbrand AV, Mehta AB, Wickremasinghe RG (1998) Herbimycin A accelerates the induction of apoptosis following etoposide treatment or gamma-irradiation of bcr/abl-positive leukaemia cells. Oncogene 16: 1533-1542. 
• Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370: 527-532. 
• Romashkova JA, Makarov SS (1999) NF-kB is a target of AKT in anti-apoptotic PDGF signaling. Nature 401: 86-90. 
• Rowley JD (1973) Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243: 290-293. 
• Rui L, Carter-Su C (1999) Identification of SH2-bbeta as a potent cytoplasmic activator of the tyrosine kinase Janus kinase 2. Proc Natl Acad Sci USA 96: 7172-7177. 
• Ruibao R (2005) Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukemia. Nat Rev Cancer 5: 172-183. 
• Sattler M, Salgia R, Okuda K, Uemura N, Durstin MA, Pisick E, 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: 839-846. 
• Savage DG, Antman KH (2002) Imatinib mesylate - a new oral targeted therapy. N Engl J Med 346: 683-693. 
• Sawyers CL (1993) The role of myc in transformation by BCR-ABL. Leuk Lymphoma 11: 45-46. 
• Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Deininger MW, Fischer T, O'Brien SG, Stone RM, Gambacorti-Passerini CB, Russell NH, Reiffers JJ, Shea TC, Chapuis B, Coutre S, Tura S, Morra E, Larson RA, Saven A, Peschel C, Gratwohl A, Mandelli F, Ben-Am M, Gathmann I, Capdeville R, Paquette RL, Druker BJ (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99: 3530-3539. 
• Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, Anania FA (2007) Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res 67: 2497-2507. 
• Scheid S, Heinzinger M, Waller CF, Lange W (1998) Bcl-2 mRNA-targeted ribozymes: effects on programmed cell death in chronic myelogenous leukemia cell lines. Ann Hematol 76: 117-125. 
• Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289: 1938-1942. 
• Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, Sawyers CL (2002) Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2: 117-125. 
• Shtivelman E, Lifshitz B, Gale RP, Canaani E (1985) Fused transcript of abl and bcr genes in chronic myeloid leukaemia. Nature 315: 550-554. 
• Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL (1996) Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene 13: 247-254. 
• Silver RT, Talpaz M, Sawyers CL (2004) Four years of follow-up of 1027 patients with late chronic phase (L-CP), accelerated phase (AP), or blast crisis (BC) chronic myeloid leukemia (Ph+CML) treated with imatinib in three large phase II trials. Blood 104: 151-160.
• Skorski T (2002) BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability. Oncogene 21: 8591-8604. 
• Skorski T (2008) BCR/ABL, DNA damage and DNA repair: implications for new treatment concepts. Leuk Lymphoma 49: 610-614. 
• 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 PI3k/Akt dependent pathway. EMBO J 16: 6151-6161. 
• Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G, Gewirtz AM, Perussia B, Calabretta B (1995) Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. Blood 86: 726-736. 
• Slupianek A, Hoser G, Majsterek I, Bronisz A, Malecki M, Blasiak J, Fishel R, Skorski T (2002) Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis. Mol Cell Biol 22: 4189-4201. 
• Sonoyama J, Matsumura I, Ezoe S, Satoh Y, Zhang X, Kataoka Y, Takai E, Mizuki M, Machii T, Wakao H, Kanakura Y (2002) Functional cooperation among Ras, STAT5, and phosphatidylinositol 3-kinase is required for full oncogenic activities of BCR/ABL in K562 cells. J Biol Chem 277: 8076-8082. 
• Squier MK, Sehnert AJ, Cohen JJ (1995) Apoptosis in leukocytes. J Leukocyte Biol 57: 2-10. 
• Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA (2004) JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia 18: 189-218. 
• Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer C, Fischer T, Deininger MW, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone R, Tura S, Mahon FX, Fernandes-Reese S, Gathmann I, Capdeville R, Kantarjian HM, Sawyers CL (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99: 1928-1937. 
• Tang TT, Dowbenko D, Jackson A, Toney L, Lewin DA, Dent AL, Lasky LA (2002) The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. J Biol Chem 277: 14255-14265. 
• Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, Hauss J, Wittekind C (2003) Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 52: 706-712. 
• Towatari M, Adachi K, Kato H, Saito H (1991) Absence of the human retinoblastoma gene product in the megakaryoblastic crisis of chronic myelogenous leukemia. Blood 78: 2178-2181. 
• Uchida N (1971) Leukokinetic studies in peripheral blood. II. Granulocyte kinetics in chronic myelocytic leukemia. Acta Haematol Japon 34: 186-204.
• Van Der Heide LP, Hoekman MF, Smidt MP (2004) The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. Biochem J 380: 297-309. 
• von Bubnoff N, Peschel C, Duyster J (2003) Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back. Leukemia 17: 829-838. 
• Walker KS, Deak M, Paterson A, Hudson K, Cohen P, Alessi DR (1998) Activation of protein kinase B beta and gamma isoforms by insulinin vivo and by 3-phosphoinositide-dependent protein kinase-1in vitro: comparison with protein kinase B alpha. Biochem J 331: 299-308. 
• Welsh GI, Hers I, Berwick DC, Dell G, Wherlock M, Birkin R, Leney S, Tavaré JM (2005) Role of protein kinase B in insulin-regulated glucose uptake. Biochem Soc Trans 33: 346-349. 
• Wilson-Rawls J, Xie SH, Liu J, Laneuville P, Arlinghaus RB (1996) P210 Bcr-Abl interacts with the interleukin-3 βc subunit and constitutively induces its tyrosine phosphorylation. Cancer Res 56: 3426-3430. 
• Wöhrle FU, Halbach S, Aumann K, Schwemmers S, Braun S, Auberger P, Schramek D, Penninger JM, Laßmann S, Werner M, Waller CF, Pahl HL, Zeiser R, Daly RJ, Brummer T (2013) Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors. Leukemia 27: 118-129. 
• Wymann MP, Pirola L (1998) Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta 1436: 127-150. 
• Xie S, Lin H, Sun T, Arlinghaus RB (2002) Jak2 is involved in c-Myc induction by Bcr-Abl. Oncogene 21: 7137-7146. 
• Xie S, Wang Y, Liu J, Sun T, Wilson MB, Smithgall TE, Arlinghaus RB (2001) Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl Transformation. Oncogene 20: 6188-6195. 
• Yao R, Cooper GM (1996) Growth factor-dependent survival of rodent fibroblasts requires phosphatidylinositol 3-kinase but is independent of pp70S6K activity. Oncogene 13: 343-351. 
• Yu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA, Backer JM (1998) Regulation of the p85/p110 phosphatidylinositol 30-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit. Mol Cell Biol 18: 1379-1387. 
• Zanetti M (2013) Cell-extrinsic effects of the tumor unfolded protein response on myeloid cells and T cells. Ann N Y Acad Sci 1284: 6-11. 
• Zhang SJ, Ma LY, Huang QH, Li G, Gu BW, Gao XD, Shi JY, Wang YY, Gao L, Cai X, Ren RB, Zhu J, Chen Z, Chen SJ (2008) Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia. Proc Natl Acad Sci USA 105: 2076-2081.