Biology of Chronic Myeloid Leukemia and Possible Therapeutic Approaches to Imatinib-Resistant Disease (original) (raw)

• Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132:1497.
  Google Scholar
• Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining [letter]. Nature. 1973;243:290–293.
  Article PubMed CAS Google Scholar
• Barnes DJ, Melo JV. Cytogenetic and molecular genetic aspects of chronic myeloid leukaemia. Acta Haematol. 2002;108:180–202.
  Article PubMed CAS Google Scholar
• Gordon MY, Dowding CR, Riley GP, Goldman JM, Greaves MF. Altered adhesive interactions with marrow stroma of haematopoietic progenitor cells in chronic myeloid leukaemia. Nature. 1987;328:342–344.
  Article CAS PubMed Google Scholar
• Bedi A, Zehnbauer BA, Barber JP, Sharkis SJ, Jones RJ. Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood. 1994;83:2038–2044.
  CAS PubMed Google Scholar
• Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996;56:100–104.
  PubMed CAS Google Scholar
• Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561–566.
  Article PubMed CAS Google Scholar
• Deininger MWN, Goldman JM, Lydon NB, Melo JV. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL positive cells. Blood. 1997;90:3691–3698.
  PubMed CAS Google Scholar
• Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925–932.
  PubMed CAS Google Scholar
• Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–1037.
  Article PubMed CAS Google Scholar
• Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–652.
  Article CAS PubMed Google Scholar
• O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronicphase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.
  Article PubMed Google Scholar
• Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038–1042.
  Article CAS PubMed Google Scholar
• Wadhwa J, Szydlo RM, Apperley JF, et al. Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia. Blood. 2002;99:2304–2309.
  Article PubMed CAS Google Scholar
• Mahon FX, Deininger MW, Schultheis B, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000;96:1070–1079.
  PubMed CAS Google Scholar
• Le Coutre P, Tassi E, Varella-Garcia M, et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood. 2000;95:1758–1766.
  PubMed Google Scholar
• Weisberg E, Griffin JD. Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood. 2000;95:3498–3505.
  PubMed CAS Google Scholar
• Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876–880.
  Article PubMed CAS Google Scholar
• Campbell LJ, Patsouris C, Rayeroux KC, Somana K, Januszewicz EH, Szer J. BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration. Cancer Genet Cytogenet. 2002;139:30–33.
  Article PubMed CAS Google Scholar
• Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16:2190–2196.
  Article PubMed CAS Google Scholar
• Mahon FX, Belloc F, Lagarde V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101:2368–2373.
  Article PubMed CAS Google Scholar
• Arceci RJ. Clinical significance of P-glycoprotein in multidrug resistance malignancies. Blood. 1993;81:2215–2222.
  PubMed CAS Google Scholar
• Vossebeld PJ, Sonneveld P. Reversal of multidrug resistance in hematological malignancies. Blood Rev. 1999;13:67–78.
  Article PubMed CAS Google Scholar
• Carulli G, Petrini M, Marini A, Ambrogi F. P-glycoprotein in acute nonlymphoblastic leukemia and in the blastic crisis of myeloid leukemia. N Engl J Med. 1988;319:797–798.
  PubMed CAS Google Scholar
• Kuwazuru Y, Yoshimura A, Hanada S, et al. Expression of the multidrug transporter, P-glycoprotein, in chronic myelogenous leukaemia cells in blast crisis. Br J Haematol. 1990;74:24–29.
  Article PubMed CAS Google Scholar
• Ferrao PT, Frost MJ, Siah SP, Ashman LK. Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro. Blood. 2003;102:4499–4503.
  Article PubMed CAS Google Scholar
• Barthe C, Cony-Makhoul P, Melo JV, Reiffers J, Mahon FX. Roots of clinical resistance to STI-571 cancer therapy. Science. 2001;293:2163.
  Article PubMed CAS Google Scholar
• Hochhaus A, Kreil S, Corbin A, et al. Roots of clinical resistance to STI-571 cancer therapy. Science. 2001;293:2163.
  Article PubMed CAS Google Scholar
• von Bubnoff N, Schneller F, Peschel C, Duyster J. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet. 2002;359:487–491.
  Article Google Scholar
• Branford S, Rudzki Z, Walsh S, et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002;99:3472–3475.
  Article CAS PubMed Google Scholar
• Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can preexist to the onset of treatment. Blood. 2002;100:1014–1018.
  Article PubMed CAS Google Scholar
• Shah NP, Nicoll JM, Nagar B, et al. 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. 2002;2:117–125.
  Article PubMed CAS Google Scholar
• Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102:276–283.
  Article PubMed CAS Google Scholar
• Hofmann WK, Jones LC, Lemp NA, et al. Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation. Blood. 2002;99:1860–1862.
  Article PubMed Google Scholar
• Goldman JM, Melo JV. Chronic myeloid leukemia: advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451–1464.
  Article PubMed CAS Google Scholar
• Tauchi T, Ohyashiki K. Molecular mechanisms of resistance of leukemia to imatinib mesylate. Leuk Res. 2004;28(suppl 1):39–45.
  Article CAS Google Scholar
• Roche-Lestienne C, Preudhomme C. Mutations in the ABL kinase domain pre-exist the onset of imatinib treatment. Semin Hematol. 2003;40:80–82.
  Article PubMed CAS Google Scholar
• Blagosklonny MV. STI-571 must select for drug-resistant cells but “no cell breathes fire out of its nostrils like a dragon.” Leukemia. 2002;16:570–572.
  Article CAS PubMed Google Scholar
• Luzzatto L, Melo JV. Acquired resistance to imatinib mesylate: selection for pre-existing mutant cells. Blood. 2002;100:1105.
  Article CAS PubMed Google Scholar
• Hofmann WK, Komor M, Wassmann B, et al. Presence of the BCR-ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in patients with Ph+ acute lymphoblastic leukemia. Blood. 2003;102:659–661.
  Article PubMed CAS Google Scholar
• Corbin AS, La Rosee P, Stoffregen EP, Druker BJ, Deininger MW. Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood. 2003;101:4611–4614.
  Article PubMed CAS Google Scholar
• Barnes DJ, Goldman JM, Melo JV. BCR-ABL expression levels determine the rate of development of resistance to imatinib mesylate (Gleevec). Blood. 2003;102:415a.
  Google Scholar
• Kantarjian HM, Talpaz M, O’Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood. 2003;101:473–475.
  Article PubMed CAS Google Scholar
• Tipping AJ, Mahon FX, Lagarde V, Goldman JM, Melo JV. Restoration of sensitivity to STI571 in STI571-resistant chronic myeloid leukemia cells. Blood. 2001;98:3864–3867.
  Article PubMed CAS Google Scholar
• Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ. Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells. Blood. 2000;96:3195–3199.
  CAS PubMed Google Scholar
• Topaly J, Fruehauf S, Ho AD, Zeller WJ. Rationale for combination therapy of chronic myelogenous leukaemia with imatinib and irradiation or alkylating agents: implications for pretransplant conditioning. Br J Cancer. 2002;86:1487–1493.
  Article PubMed PubMed Central CAS Google Scholar
• Fang G, Kim CN, Perkins CL, et al. CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs. Blood. 2000;96:2246–2253.
  PubMed CAS Google Scholar
• Kano Y, Akutsu M, Tsunoda S, et al. In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents. Blood. 2001;97:1999–2007.
  Article PubMed CAS Google Scholar
• Topaly J, Zeller WJ, Fruehauf S. Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells. Leukemia. 2001;15:342–347.
  Article CAS PubMed Google Scholar
• Scappini B, Onida F, Kantarjian HM, et al. In vitro effects of STI 571-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells. Cancer. 2002;94:2653–2662.
  Article PubMed CAS Google Scholar
• Gardembas M, Rousselot P, Tulliez M, et al. Results of a prospective phase II study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase. Blood. 2003;102:4298–4305.
  Article PubMed CAS Google Scholar
• Tipping AJ, Mahon FX, Zafirides G, Lagarde V, Goldman JM, Melo JV. Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs. Leukemia. 2002;16:2349–2357.
  Article PubMed CAS Google Scholar
• Kaur G, Gazit A, Levitzki A, Stowe E, Cooney DA, Sausville EA. Tyrphostin induced growth inhibition: correlation with effect on p210bcr-abl autokinase activity in K562 chronic myelogenous leukemia. Anticancer Drugs. 1994;5:213–222.
  Article PubMed CAS Google Scholar
• Svingen PA, Tefferi A, Kottke TJ, et al. Effects of the bcr/abl kinase inhibitors AG957 and NSC 680410 on chronic myelogenous leukemia cells in vitro. Clin Cancer Res. 2000;6:237–249.
  CAS PubMed Google Scholar
• Mow BM, Chandra J, Svingen PA, et al. Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro. Blood. 2002;99:664–671.
  Article PubMed CAS Google Scholar
• Nimmanapalli R, O’Bryan E, Bhalla K. Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. Cancer Res. 2001;61:1799–1804.
  PubMed CAS Google Scholar
• An WG, Schulte TW, Neckers LM. The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210bcr-abl and v-src proteins before their degradation by the proteasome. Cell Growth Differ. 2000;11:355–360.
  PubMed CAS Google Scholar
• Blagosklonny MV, Fojo T, Bhalla KN, et al. The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy. Leukemia. 2001;15:1537–1543.
  Article PubMed CAS Google Scholar
• Gorre ME, Ellwood-Yen K, Chiosis G, Rosen N, Sawyers CL. BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood. 2002;100:3041–3044.
  Article PubMed CAS Google Scholar
• Topaly J, Schad M, Laufs S, Melo JV, Zeller WJ, Fruehauf S. Crossresistance of imatinib mesylate and 17-AAG in imatinib-resistant cells that overexpress BCR-ABL. Br J Haematol. 2003;121:672–673.
  Article PubMed Google Scholar
• Needleman SW, Gutheil JC, Kapil V, Mane SM. Infrequent ras activation in chronic myelogenous leukemia (CML): activating 61st codon mutation in the CML-derived cell line, IM-9. Leukemia. 1989;3:827–829.
  PubMed CAS Google Scholar
• Watzinger F, Gaiger A, Karlic H, Becher R, Pillwein K, Lion T. Absence of N-ras mutations in myeloid and lymphoid blast crisis of chronic myeloid leukemia. Cancer Res. 1994;54:3934–3938.
  PubMed CAS Google Scholar
• Druker B, Okuda K, Matulonis U, Salgia R, Roberts T, Griffin JD. Tyrosine phosphorylation of rasGAP and associated proteins in chronic myelogenous leukemia cell lines. Blood. 1992;79:2215–2220.
  PubMed CAS Google Scholar
• Sakai N, Ogiso Y, Fujita H, Watari H, Koike T, Kuzumaki N. Induction of apoptosis by a dominant negative H-RAS mutant (116Y) in K562 cells. Exp Cell Res. 1994;215:131–136.
  Article PubMed CAS Google Scholar
• Adjei AA, Erlichman C, Davis JN, et al. A phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity. Cancer Res. 2000;60:1871–1877.
  PubMed CAS Google Scholar
• Awada A, Eskens FA, Piccart M, et al. Phase I and pharmacological study of the oral farnesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours. Eur J Cancer. 2002;38:2272–2278.
  Article PubMed CAS Google Scholar
• Sharma S, Kemeny N, Kelsen DP, et al. A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan. Ann Oncol. 2002;13:1067–1071.
  Article PubMed CAS Google Scholar
• Reichert A, Heisterkamp N, Daley GQ, Groffen J. Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336. Blood. 2001;97:1399–1403.
  Article PubMed CAS Google Scholar
• Peters DG, Hoover RR, Gerlach MJ, et al. Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. Blood. 2001;97:1404–1412.
  Article PubMed CAS Google Scholar
• Hoover RR, Mahon FX, Melo JV, Daley GQ. Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336. Blood. 2002;100:1068–1071.
  Article PubMed CAS Google Scholar
• Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood. 2001;97:3361–3369.
  Article PubMed CAS Google Scholar
• Cortes J, AlBitar M, Thomas D, et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood. 2003;101:1692–1697.
  Article PubMed CAS Google Scholar
• Kuroda J, Kimura S, Segawa H, et al. The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate. Blood. 2003;102:2229–2235.
  Article PubMed CAS Google Scholar
• Chuah C, Tipping AJ, Goldman JM, Melo JV. Zoledronate is active against imatinib mesylate-resistant chronic myeloid leukemia cell lines and synergistic/additive when combined with imatinib mesylate. Blood. 2003;102:19a.
  Google Scholar
• de Groot RP, Raaijmakers JA, Lammers JW, Jove R, Koenderman L. STAT5 activation by BCR-Abl contributes to transformation of K562 leukemia cells. Blood. 1999;94:1108–1112.
  PubMed Google Scholar
• Kraker AJ, Hartl BG, Amar AM, Barvian MR, Showalter HD, Moore CW. Biochemical and cellular effects of c-Src kinase-selective pyrido[2, 3-d]pyrimidine tyrosine kinase inhibitors. Biochem Pharmacol. 2000;60:885–898.
  Article PubMed CAS Google Scholar
• Dorsey JF, Jove R, Kraker AJ, Wu J. The pyrido[2,3-d]pyrimidine derivative PD180970 inhibits p210Bcr-Abl tyrosine kinase and induces apoptosis of K562 leukemic cells. Cancer Res. 2000;60:3127–3131.
  PubMed CAS Google Scholar
• Huang M, Dorsey JF, Epling-Burnette PK, et al. Inhibition of Bcr-Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells. Oncogene. 2002;21:8804–8816.
  Article PubMed CAS Google Scholar
• Nimmanapalli R, O’Bryan E, Huang M, et al. Molecular characterization and sensitivity of STI-571 (imatinib mesylate, Gleevec)-resistant, Bcr-Abl-positive, human acute leukemia cells to SRC kinase inhibitor PD180970 and 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 2002;62:5761–5769.
  PubMed CAS Google Scholar
• La Rosee P, Corbin AS, Stoffregen EP, Deininger MW, Druker BJ. Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). Cancer Res. 2002;62:7149–7153.
  PubMed Google Scholar
• Wisniewski D, Lambek CL, Liu C, et al. Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases. Cancer Res. 2002;62:4244–4255.
  PubMed CAS Google Scholar
• von Bubnoff N, Veach DR, Miller WT, et al. Inhibition of wild-type and mutant Bcr-Abl by pyrido-pyrimidine-type small molecule kinase inhibitors. Cancer Res. 2003;63:6395–6404.
  Google Scholar
• Huron DR, Gorre ME, Kraker AJ, Sawyers CL, Rosen N, Moasser MM. A novel pyridopyrimidine inhibitor of abl kinase is a picomolar inhibitor of Bcr-abl-driven K562 cells and is effective against STI571-resistant Bcr-abl mutants. Clin Cancer Res. 2003;9:1267–1273.
  PubMed CAS Google Scholar
• Skorski T, Kanakaraj P, Nieborowska-Skorska M, et al. Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. Blood. 1995;86:726–736.
  PubMed CAS Google Scholar
• Klejman A, Rushen L, Morrione A, Slupianek A, Skorski T. Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. Oncogene. 2002;21:5868–5876.
  Article PubMed CAS Google Scholar
• Ly C, Arechiga AF, Melo JV, Walsh CM, Ong ST. Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res. 2003;63:5716–5722.
  PubMed CAS Google Scholar
• Kuypers DR, Herelixka A, Vanrenterghem Y. Clinical use of rapamycin in renal allograft recipients identifies its relevant toxicity profile and raises unsolved questions: a single-center experience. Transplant Proc. 2003;35:138S-142S.
  Article PubMed CAS Google Scholar
• Dan S, Naito M, Tsuruo T. Selective induction of apoptosis in Philadelphia chromosome-positive chronic myelogenous leukemia cells by an inhibitor of BCR-ABL tyrosine kinase, CGP 57148. Cell Death Differ. 1998;5:710–715.
  Article PubMed CAS Google Scholar
• Kang CD, Yoo SD, Hwang BW, et al. The inhibition of ERK/ MAPK not the activation of JNK/SAPK is primarily required to induce apoptosis in chronic myelogenous leukemic K562 cells. Leuk Res. 2000;24:527–534.
  Article PubMed CAS Google Scholar
• Yu C, Krystal G, Varticovksi L, et al. Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/ mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells. Cancer Res. 2002;62:188–199.
  PubMed CAS Google Scholar
• Chu S, Holtz M, Gupta M, Bhatia R. BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells. Blood. 2004;103:3167–3174.
  Article PubMed CAS Google Scholar
• Ward AC, Touw I, Yoshimura A. The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood. 2000;95:19–29.
  PubMed CAS Google Scholar
• Wilson-Rawls J, Xie S, Liu J, Laneuville P, Arlinghaus RB. P210 Bcr-Abl interacts with the interleukin 3 receptor beta(c) subunit and constitutively induces its tyrosine phosphorylation. Cancer Res. 1996;56:3426–3430.
  PubMed CAS Google Scholar
• Wilson-Rawls J, Liu J, Laneuville P, Arlinghaus RB. P210 Bcr-Abl interacts with the interleukin-3 beta c subunit and constitutively activates Jak2. Leukemia. 1997;11(suppl 3):428–431.
  PubMed Google Scholar
• Xie S, Wang Y, Liu J, et al. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene. 2001;20:6188–6195.
  Article PubMed CAS Google Scholar
• Meydan N, Grunberger T, Dadi H, et al. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature. 1996;379:645–648.
  Article PubMed CAS Google Scholar
• Sun X, Layton JE, Elefanty A, Lieschke GJ. Comparison of effects of the tyrosine kinase inhibitors AG957, AG490, and STI571 on BCR-ABL-expressing cells, demonstrating synergy between AG490 and STI571. Blood. 2001;97:2008–2015.
  Article PubMed CAS Google Scholar
• Marley SB, Davidson RJ, Goldman JM, Gordon MY. Effects of combinations of therapeutic agents on the proliferation of progenitor cells in chronic myeloid leukaemia. Br J Haematol. 2002;116:162–165.
  Article PubMed CAS Google Scholar
• Griffith TS, Lynch DH. TRAIL: a molecule with multiple receptors and control mechanisms. Curr Opin Immunol. 1998;10:559–563.
  Article PubMed CAS Google Scholar
• Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995;3:673–682.
  Article PubMed CAS Google Scholar
• Thomas WD, Hersey P. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells. J Immunol. 1998;161:2195–2200.
  PubMed CAS Google Scholar
• Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science. 1997;277:815–818.
  Article PubMed CAS Google Scholar
• Nimmanapalli R, Porosnicu M, Nguyen D, et al. Cotreatment with STI-571 enhances tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL or apo-2L)-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Clin Cancer Res. 2001;7:350–357.
  PubMed CAS Google Scholar
• Uno K, Inukai T, Kayagaki N, et al. TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells. Blood. 2003;101:3658–3667.
  Article PubMed CAS Google Scholar
• Cress WD, Seto E. Histone deacetylases, transcriptional control, and cancer. J Cell Physiol. 2000;184:1–16.
  Article PubMed CAS Google Scholar
• Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA. 2000;97:10014–10019.
  Article PubMed PubMed Central CAS Google Scholar
• Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst. 2000;92:1210–1216.
  Article PubMed CAS Google Scholar
• Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood. 2003;101:3236–3239.
  Article PubMed CAS Google Scholar
• Yu C, Rahmani M, Almenara J, et al. Histone deacetylase inhibitors promote STI571-mediated apoptosis in STI571-sensitive and -resistant Bcr/Abl+ human myeloid leukemia cells. Cancer Res. 2003;63:2118–2126.
  PubMed CAS Google Scholar
• Nimmanapalli R, Fuino L, Bali P, et al. Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or-refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res. 2003;63:5126–5135.
  PubMed CAS Google Scholar
• Almond JB, Cohen GM. The proteasome: a novel target for cancer chemotherapy. Leukemia. 2002;16:433–443.
  Article PubMed CAS Google Scholar
• King RW, Deshaies RJ, Peters JM, Kirschner MW. How proteolysis drives the cell cycle. Science. 1996;274:1652–1659.
  Article PubMed CAS Google Scholar
• Jonuleit T, van der KH, Miething C, et al. Bcr-Abl kinase down-regulates cyclin-dependent kinase inhibitor p27 in human and murine cell lines. Blood. 2000;96:1933–1939.
  PubMed CAS Google Scholar
• Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin AS Jr. A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation. Genes Dev. 1998;12:968–981.
  Article PubMed PubMed Central CAS Google Scholar
• Hamdane M, David-Cordonnier MH, D’Halluin JC. Activation of p65 NF-kappaB protein by p210BCR-ABL in a myeloid cell line (P210BCR-ABL activates p65 NF-kappaB). Oncogene. 1997;15:2267–2275.
  Article PubMed CAS Google Scholar
• Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999;59:2615–2622.
  PubMed CAS Google Scholar
• Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609–2617.
  Article PubMed CAS Google Scholar
• Gatto S, Scappini B, Pham L, et al. The proteasome inhibitor PS-341 inhibits growth and induces apoptosis in Bcr/Abl-positive cell lines sensitive and resistant to imatinib mesylate. Haematologica. 2003;88:853–863.
  PubMed CAS Google Scholar
• Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood. 2003;102:3765–3774.
  Article PubMed CAS Google Scholar
• Arguello F, Alexander M, Sterry JA, et al. Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity in vivo against human leukemia and lymphoma xenografts. Blood. 1998;91:2482–2490.
  PubMed CAS Google Scholar
• Yu C, Krystal G, Dent P, Grant S. Flavopiridol potentiates STI571-induced mitochondrial damage and apoptosis in BCR-ABL-positive human leukemia cells. Clin Cancer Res. 2002;8:2976–2984.
  PubMed CAS Google Scholar
• Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL), II: clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:3354–3360.
  PubMed CAS Google Scholar
• Puccetti E, Guller S, Orleth A, et al. BCR-ABL mediates arsenic trioxide-induced apoptosis independently of its aberrant kinase activity. Cancer Res. 2000;60:3409–3413.
  PubMed CAS Google Scholar
• Perkins C, Kim CN, Fang G, Bhalla KN. Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L). Blood. 2000;95:1014–1022.
  PubMed CAS Google Scholar
• Nimmanapalli R, Bali P, O’Bryan E, et al. Arsenic trioxide inhibits translation of mRNA of bcr-abl, resulting in attenuation of Bcr-Abl levels and apoptosis of human leukemia cells. Cancer Res. 2003;63:7950–7958.
  PubMed CAS Google Scholar
• La Rosee P, Johnson K, O’Dwyer ME, Druker BJ. In vitro studies of the combination of imatinib mesylate (Gleevec) and arsenic trioxide (Trisenox) in chronic myelogenous leukemia. Exp Hematol. 2002;30:729–737.
  Article PubMed Google Scholar
• La Rosee P, Johnson K, Corbin AS, et al. In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl-positive cell lines. Blood. 2004;103:208–215.
  Article PubMed CAS Google Scholar
• Kantarjian HM, O’Brien SM, Keating M, et al. Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. Leukemia. 1997;11:1617–1620.
  Article PubMed CAS Google Scholar
• Kantarjian HM, O’Brien S, Cortes J, et al. Results of decitabine (5-aza-2′deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer. 2003;98:522–528.
  Article PubMed CAS Google Scholar
• Giles FJ, Feldman EJ, Roboz GJ, et al. Phase II study of troxacitabine, a novel dioxolane nucleoside analog, in patients with untreated or imatinib mesylate-resistant chronic myelogenous leukemia in blastic phase. Leuk Res. 2003;27:1091–1096.
  Article PubMed CAS Google Scholar
• McWhirter JR, Wang JY. An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias. EMBO J. 1993;12:1533–1546.
  Article PubMed PubMed Central CAS Google Scholar
• Wen ST, Jackson PK, Van Etten RA. The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products. EMBO J. 1996;15:1583–1595.
  Article PubMed PubMed Central CAS Google Scholar
• Taagepera S, McDonald D, Loeb JE, et al. Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase. Proc Natl Acad Sci USA. 1998;95:7457–7462.
  Article PubMed PubMed Central CAS Google Scholar
• Fornerod M, Ohno M, Yoshida M, Mattaj IW. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997;90:1051–1060.
  Article PubMed CAS Google Scholar
• Fukuda M, Asano S, Nakamura T, et al. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature. 1997;390:308–311.
  Article PubMed CAS Google Scholar
• McGahon A, Bissonnette R, Schmitt M, Cotter KM, Green DR, Cotter TG. BCR-ABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death [published correction appears in Blood. 1994;83:3835]. Blood. 1994;83:1179–1187.
  PubMed CAS Google Scholar
• Vigneri P, Wang JY. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med. 2001;7:228–234.
  Article PubMed CAS Google Scholar
• Newlands ES, Rustin GJ, Brampton MH. Phase I trial of elactocin. Br J Cancer. 1996;74:648–649.
  Article PubMed PubMed Central CAS Google Scholar
• Skorski T, Nieborowska-Skorska M, Nicolaides NC, et al. Suppression of Philadelphia1 leukemia cell growth in mice by BCR-ABL antisense oligodeoxynucleotide. Proc Natl Acad Sci USA. 1994;91:4504–4508.
  Article PubMed PubMed Central CAS Google Scholar
• De Fabritiis P, Petti MC, Montefusco E, et al. BCR-ABL antisense oligodeoxynucleotide in vitro purging and autologous bone marrow transplantation for patients with chronic myelogenous leukemia in advanced phase. Blood. 1998;91:3156–3162.
  PubMed Google Scholar
• James HA, Gibson I. The therapeutic potential of ribozymes. Blood. 1998;91:371–382.
  PubMed CAS Google Scholar
• Kuwabara T, Warashina M, Tanabe T, Tani K, Asano S, Taira K. A novel allosterically trans-activated ribozyme, the maxizyme, with exceptional specificity in vitro and in vivo. Mol Cell. 1998;2:617–627.
  Article PubMed CAS Google Scholar
• Tanabe T, Kuwabara T, Warashina M, Tani K, Taira K, Asano S. Oncogene inactivation in a mouse model. Nature. 2000;406:473–474.
  Article PubMed CAS Google Scholar
• Wu Y, Yu L, McMahon R, Rossi JJ, Forman SJ, Snyder DS. Inhibition of bcr-abl oncogene expression by novel deoxyribozymes (DNAzymes). Hum Gene Ther. 1999;10:2847–2857.
  Article PubMed CAS Google Scholar
• Hannon GJ. RNA interference. Nature. 2002;418:244–251.
  Article PubMed CAS Google Scholar
• Zamore PD. Ancient pathways programmed by small RNAs. Science. 2002;296:1265–1269.
  Article PubMed CAS Google Scholar
• Hammond SM, Bernstein E, Beach D, Hannon GJ. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature. 2000;404:293–296.
  Article PubMed CAS Google Scholar
• Bernstein E, Caudy AA, Hammond SM, Hannon GJ. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature. 2001;409:363–366.
  Article PubMed CAS Google Scholar
• Scherr M, Battmer K, Winkler T, Heidenreich O, Ganser A, Eder M. Specific inhibition of bcr-abl gene expression by small interfering RNA. Blood. 2003;101:1566–1569.
  Article PubMed CAS Google Scholar
• Wohlbold L, van der KH, Miething C, et al. Inhibition of bcr-abl gene expression by small interfering RNA sensitizes for imatinib mesylate (STI571). Blood. 2003;102:2236–2239.
  Article PubMed CAS Google Scholar
• Bocchia M, Wentworth PA, Southwood S, et al. Specific binding of leukemia oncogene fusion protein peptides to HLA class I molecules. Blood. 1995;85:2680–2684.
  PubMed CAS Google Scholar
• Bosch GJ, Joosten AM, Kessler JH, Melief CJ, Leeksma OC. Recognition of BCR-ABL positive leukemic blasts by human CD4+ T cells elicited by primary in vitro immunization with a BCR-ABL breakpoint peptide. Blood. 1996;88:3522–3527.
  PubMed CAS Google Scholar
• Pawelec G, Max H, Halder T, et al. BCR/ABL leukemia oncogene fusion peptides selectively bind to certain HLA-DR alleles and can be recognized by T cells found at low frequency in the repertoire of normal donors. Blood. 1996;88:2118–2124.
  PubMed CAS Google Scholar
• Mannering SI, McKenzie JL, Fearnley DB, Hart DN. HLA-DR1-restricted bcr-abl (b3a2)-specific CD4+ T lymphocytes respond to dendritic cells pulsed with b3a2 peptide and antigenpresenting cells exposed to b3a2 containing cell lysates. Blood. 1997;90:290–297.
  PubMed CAS Google Scholar
• Pinilla-Ibarz J, Cathcart K, Korontsvit T, et al. Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. Blood. 2000;95:1781–1787.
  PubMed CAS Google Scholar
• Cathcart K, Pinilla-Ibarz J, Korontsvit T, et al. A multivalent bcr-abl fusion peptide vaccination trial in patients with chronic myeloid leukemia. Blood. 2004;103:1037–1042.
  Article PubMed CAS Google Scholar
• Gao L, Bellantuono I, Elsasser A, et al. Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood. 2000;95:2198–2203.
  PubMed CAS Google Scholar
• Amrolia PJ, Reid SD, Gao L, et al. Allorestricted cytotoxic T cells specific for human CD45 show potent antileukemic activity. Blood. 2003;101:1007–1014.
  Article PubMed CAS Google Scholar
• El Ouriaghli F, Fujiwara H, Melenhorst JJ, Sconocchia G, Hensel N, Barrett AJ. Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF: implications for the regulation of granulopoiesis. Blood. 2003;101:1752–1758.
  Article PubMed CAS Google Scholar
• El Ouriaghli F, Sloand E, Main waring L, et al. Clonal dominance of chronic myelogenous leukemia is associated with diminished sensitivity to the antiproliferative effects of neutrophil elastase. Blood. 2003;102:3786–3792.
  Article CAS PubMed Google Scholar
• Fujiwara H, El Ouriaghli F, Grube M, et al. Identification and in vitro expansion of CD4+ and CD8+ T cells specific for human neutrophil elastase. Blood. 2004;103:3076–3083.
  Article PubMed CAS Google Scholar
• Molldrem JJ, Clave E, Jiang YZ, et al. Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colony-forming units. Blood. 1997;90:2529–2534.
  PubMed CAS Google Scholar
• Molldrem JJ, Lee PP, Wang C, et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med. 2000;6:1018–1023.
  Article CAS PubMed Google Scholar