Abstract
Leukemia is a group of heterozygous diseases of hematopoietic stem/progenitor cells that involves dynamic change in the genome. Dissection of genetic abnormalities critical to leukemia initiation provides insights into the elusive leukemogenesis, identifies distinct subsets of leukemia and predicts prognosis individually, and can also provide rational therapeutic targets for curative approaches. The past three decades have seen tremendous advances in the analysis of genotype–phenotype connection of leukemia, and in the identification of molecular biomarkers for leukemia subtypes. Intriguingly, differentiation therapy, targeted therapy and chemotherapy have turned several subtypes of leukemia from highly fatal to highly curable. The use of all-trans retinoic acid and arsenic trioxide, which trigger degradation of PML-RARα, the causative fusion protein generated by t (15;17) translocation in acute promyelocytic leukemia (APL), has led to a dramatic improvement of APL clinical outcome. Imatinib mesylate/ Gleevec/STI571, which inhibits the tyrosine kinase activity of BCR-ABL oncoprotein, has now become the new gold standard for the treatmtent of chronic myeloid leukemia. Optimal use of chemotherapeutic agents together with a stringent application of prognostic factors for risk-directed therapy in clinical trials has resulted in a steady improvement in the treatment outcome of acute lymphoblastic leukemia. Hence, the pace of progress extrapolates to a prediction of leukemia control in the twenty-first century.
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Parkin DM, Bray F, Ferlay J, Pisani P . Global Cancer Statistics, 2002. CA Cancer J Clin 2005; 55: 74–108.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103: 620–5.
Licht JD, Sternberg DW . The molecular pathology of acute myeloid leukemia. Hematology 2005; 2005: 137–42.
Pui CH, Jeha S . New therapeutic strategies for the treatment of acute lymphoblastic leukaemia. Nat Rev Drug Discov 2007; 6: 149–65.
Zhou GB, Zhao WL, Wang ZY, Chen SJ, Chen Z . Retinoic acid and arsenic for treating acute promyelocytic leukemia. PLoS Med 2005; 2: 33–8.
Chen SJ, Zhu YJ, Tong JH, Dong S, Huang W, Chen Y, et al. Rearrangements in the second intron of the RARA gene are present in a large majority of patients with acute promyelocytic leukemia and are used as molecular marker for retinoic acid-induced leukemic cell differentiation. Blood 1991; 78: 2696–701.
Wang Y Y, Zhou GB, Yin T, Chen B, Shi JY, Liang WX, et al. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: Implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci USA 2005; 102: 1104–9.
Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati T, Pasqualucci L, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352: 254–66.
Gebhard C, Schwarzfischer L, Pham TH, Schilling E, Klug M, Andreesen R, et al. Genome-wide profiling of CpG methylation identifies novel targets of aberrant hypermethylation in myeloid leukemia. Cancer Res 2006; 66: 6118–28.
Mrozek K, Bloomfield CD . Chromosome aberrations, gene mutations and expression changes, and prognosis in adult acute myeloid leukemia. Hematology 2006; 2006: 169–77.
Zhou GB, Kang H, Wang L, Gao L, Liu P, Xie J, et al. Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8; 21) leukemia in vitro and in vivo. Blood 2007; 109: 3441–50.
Wang L, Zhao WL, Yan JS, Liu P, Sun H P, Zhou GB, et al. Eriocalyxin B induces apoptosis of t(8; 21) leukemia cells through NF-kappaB and MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner. Cell Death Differ 2007; 14: 306–17.
Yang G, Thompson MA, Brandt SJ, Hiebert SW . Histone deacetylase inhibitors induce the degradation of the t(8; 21) fusion oncoprotein. Oncogene 2007; 26: 91–101.
Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567–72.
Chen GQ, Zhu J, Shi XG, Ni JH, Zhong HJ, Si GY, et al. In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Blood 1996; 88: 1052–61.
Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 1997; 89: 3345–53.
Yan M, Kanbe E, Peterson LF, Boyapati A, Miao Y, Wang Y, et al. A previously unidentified alternatively spliced isoform of t(8; 21) transcript promotes leukemogenesis. Nat Med 2006; 12: 945–9.
Sobulo OM, Borrow J, Tomek R, Reshmi S, Harden A, Schlegelberger B, et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with at(11; 16)(q23; p13.3). Proc Natl Acad Sci USA 1997; 94: 8732–7.
Tkachuk DC, Kohler S, Cleary ML . Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 1992; 71: 691–700.
Thirman MJ, Levitan DA, Kobayashi H, Simon MC, Rowley JD . Cloning of ELL, a gene that fuses to MLL in a t(11; 19)(q23; p13.1) in acute myeloid leukemia. Proc Natl Acad Sci USA 1994; 91: 12110–4.
Talpaz M, Shah N P, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006; 354: 2531–41.
Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, et al. Nilotinib in Imatinib-Resistant CML and Philadelphia Chromosome-Positive ALL. N Engl J Med 2006; 354: 2542–51.
Carroll WL, Bhojwani D, Min DJ, Raetz E, Relling M, Davies S, et al. Pediatric acute lymphoblastic leukemia. Hematology 2003; 2003: 102–31.
Pui CH, Evans WE . Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354: 166–78.
Kau TR, Way JC, Silver PA . Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer 2004; 4: 106–17.
Chen Z, Chen SJ, Tong JH, Zhu YJ, Huang ME, Wang WC, et al. The retinoic acid alpha receptor gene is frequently disrupted in its 5′ part in Chinese patients with acute promyelocytic leukemia. Leukemia 1991; 5: 288–92.
Tong JH, Dong S, Geng J P, Huang W, Wang Z Y, Sun GL, et al. Molecular rearrangements of the MYL gene in acute promyelocytic leukemia (APL, M3) define a breakpoint cluster region as well as some molecular variants. Oncogene 1992; 7: 311–6.
Chen Z, Chen SJ . RARalpha and PML genes in acute promyelocytic leukemia. Leuk Lymphoma 1992; 8: 253–60.
Qiang B . Human genome research in China. J Mol Med 2004; 82: 214–22.
de TH, Chomienne C, Lanotte M, Degos L, Dejean A . The t(15; 17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 1990; 347: 558–61.
Kakizuka A, Miller WH Jr, Umesono K, Warrell RP, Frankel SR, Murty VV, et al. Chromosomal translocation t(15; 17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 1991; 66: 663–74.
Chen SJ, Chen Z, Chen A, Tong JH, Dong S, Wang ZY, et al. Occurrence of distinct PML-RAR-alpha fusion gene isoforms in patients with acute promyelocytic leukemia detected by reverse transcriptase/polymerase chain reaction. Oncogene 1992; 7: 1223–32.
Geng J P, Tong JH, Dong S, Wang ZY, Chen SJ, Chen Z, et al. Localization of the chromosome 15 breakpoints and expression of multiple PML-RAR alpha transcripts in acute promyelocytic leukemia: a study of 28 Chinese patients. Leukemia 1993; 7: 20–6.
Gu BW, Hu J, Xu L, Yan H, Jin WR, Zhu YM, et al. Feasibility and clinical significance of real-time quantitative RT-PCR assay of PML-RARalpha fusion transcript in patients with acute promyelocytic leukemia. Hematol J 2001; 2: 330–40.
Gu BW, Xiong H, Zhou Y, Chen B, Wang L, Dong S, et al. Variant-type PML-RAR(alpha) fusion transcript in acute promyelocytic leukemia: use of a cryptic coding sequence from intron 2 of the RAR(alpha) gene and identification of a new clinical subtype resistant to retinoic acid therapy. Proc Natl Acad Sci USA 2002; 99: 7640–5.
Melnick A, Licht JD . Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999; 93: 3167–215.
Xu L, Zhao WL, Xiong SM, Su XY, Zhao M, Wang C, et al. Molecular cytogenetic characterization and clinical relevance of additional, complex and/or variant chromosome abnormalities in acute promyelocytic leukemia. Leukemia 2001; 15: 1359–68.
Chen SJ, Zelent A, Tong JH, Yu HQ, Wang ZY, Derre J, et al. Rearrangements of the retinoic acid receptor alpha and promyelocytic leukemia zinc finger genes resulting from t(11; 17)(q23; q21) in a patient with acute promyelocytic leukemia. J Clin Invest 1993; 91: 2260–7.
Chen Z, Brand NJ, Chen A, Chen S J, Tong JH, Wang ZY, et al. Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11; 17) translocation associated with acute promyelocytic leukaemia. EMBO J 1993; 12: 1161–7.
Zhang T, Xiong H, Kan LX, Zhang CK, Jiao XF, Fu G, et al. Genomic sequence, structural organization, molecular evolution, and aberrant rearrangement of promyelocytic leukemia zinc finger gene. Proc Natl Acad Sci USA 1999; 96: 11422–7.
Chen Z, Guidez F, Rousselot P et al. PLZF-RAR alpha fusion proteins generated from the variant t(11; 17)(q23; q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors. Proc Natl Acad Sci USA 1994; 91: 1178–82.
Zhou GB, Chen SJ, Chen Z . Acute promyelocytic leukemia: a model of molecular target based therapy. Hematology 2005; 10 Suppl 1: 270–80.
Grisolano JL, Wesselschmidt RL, Pelicci PG, Ley TJ . Altered myeloid development and acute leukemia in transgenic mice expressing PML-RAR alpha under control of cathepsin G regulatory sequences. Blood 1997; 89: 376–87.
Cheng GX, Zhu XH, Men XQ, Wang L, Huang QH, Jin XL, et al. Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARalpha and NPM-RARalpha. Proc Natl Acad Sci USA 1999; 96: 6318–23.
Chen LJ, Dong Y, Chen SY, Zhang L, Zhou GB, Chen B, et al. hCG-PLZF-RARalpha/hCG-RARalpha-PLZF transgenic mice developing into leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2005; 13: 924–31. Chinese.
Niu C, Yan H, Yu T, Sun H P, Liu JX, Li XS, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999; 94: 3315–24.
Zhang P, Wang SY, Hu LH . Arsenic trioxide treated 72 cases of acute promyelocytic leukemia. Chin J Hematol 1995; 17: 58–62.
Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, 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: 3354–60.
Sun HD, Ma L, Hu XC, Zhang TD . Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integrat Chin West Med 1992; 12: 170–1.
Fang J, Chen SJ, Tong JH, Wang ZG, Chen GQ, Chen Z, et al. Treatment of acute promyelocytic leukemia with ATRA and As2O3: a model of molecular target-based cancer therapy. Cancer Biol Ther 2002; 1: 614–20.
Zhang JW, Wang JY, Chen SJ, Chen Z . Mechanisms of all-trans retinoic acid-induced differentiation of acute promyelocytic leukemia cells. J Biosci 2000; 25: 275–84.
Zhu J, Chen Z, Lallemand-Breitenbach V, de The H . How acute promyelocytic leukaemia revived arsenic. Nat Rev Cancer 2002; 2: 705–13.
Zhou G, Zhang J, Wang Z, Chen S, Chen Z . Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy. Phil Trans R Soc B 2007; 362: 959–71.
Chen Z, Chen GQ, Shen ZX, Chen SJ, Wang ZY . Treatment of acute promyelocytic leukemia with arsenic compounds: in vitro and in vivo studies. Semin Hematol 2001; 38: 26–36.
Chen Z, Tong JH, Dong S, Zhu J, Wang ZY, Chen SJ. et al. Retinoic acid regulatory pathways, chromosomal translocations, and acute promyelocytic leukemia. Genes Chromosomes Cancer 1996; 15: 147–56.
Chen Z, Wang ZY, Chen SJ . Acute promyelocytic leukemia: cellular and molecular basis of differentiation and apoptosis. Pharmacol Ther 1997; 76: 141–9.
Nervi C, Ferrara FF, Fanelli M, Rippo MR, Tomassini B, Ferrucci PF, et al. Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARalpha fusion protein. Blood 1998; 92: 2244–51.
Brown D, Kogan S, Lagasse E, Weissman I, Alcalay M, Pelicci PG, et al. A PMLRARalpha transgene initiates murine acute promyelocytic leukemia. Proc Natl Acad Sci USA 1997; 94: 2551–6.
vom BE, Zechel C, Heery D, Heine MJ, Garnier JM, Vivat V, et al. Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1. EMBO J 1996; 15: 110–24.
Kamashev D, Vitoux D, de The H . PML-RARalpha-RXR oligomers mediate retinoid and rexinoid/cAMP cross-talk in acute promyelocytic leukemia cell differentiation. J Exp Med 2004; 199: 1163–74.
Garzon R, Pichiorri F, Palumbo T, Visentini M, Aqeilan R, Cimmino A, et al. MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene 2007; 26: 4148–57.
Rocca B, Morosetti R, Habib A, Maggiano N, Zassadowski F, Ciabattoni G, et al. Cyclooxygenase-1, but not -2, is upregulated in NB4 leukemic cells and human primary promyelocytic blasts during differentiation. Leukemia 2004; 18: 1373–9.
Kini AR, Peterson LA, Tallman MS, Lingen MW . Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid. Blood 2001; 97: 3919–24.
Zhu J, Guo WM, Yao YY, Zhao WL, Pan L, Cai X, et al. Tissue factors on acute promyelocytic leukemia and endothelial cells are differently regulated by retinoic acid, arsenic trioxide and chemotherapeutic agents. Leukemia 1999; 13: 1062–70.
Xiao S, Li D, Zhu HQ, Song MG, Pan XR, Jia PM, et al. RIG-G as a key mediator of the antiproliferative activity of interferon-related pathways through enhancing p21 and p27 proteins. Proc Natl Acad Sci USA 2006; 103: 16448–53.
Mao M, Yu M, Tong JH, Ye J, Zhu J, Huang QH, et al. RIG-E, a human homolog of the murine Ly-6 family, is induced by retinoic acid during the differentiation of acute promyelocytic leukemia cell. Proc Natl Acad Sci USA 1996; 93: 5910–4.
Yu M, Tong JH, Mao M, Kan LX, Liu MM, Sun YW, et al. Cloning of a gene (RIG-G) associated with retinoic acid-induced differentiation of acute promyelocytic leukemia cells and representing a new member of a family of interferon-stimulated genes. Proc Natl Acad Sci USA 1997; 94: 7406–11.
Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 2004; 5: 730–7.
Liu TX, Zhang J W, Tao J, Zhang RB, Zhang QH, Zhao CJ, et al. Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells. Blood 2000; 96: 1496–504.
Zhu J, Koken MH, Quignon F, Chelbi-Alix MK, Degos L, Wang ZY, et al. Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc Natl Acad Sci USA 1997; 94: 3978–83.
Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honoré N, Doubeikovsky A, et al. Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor alpha degradation. J Exp Med 2001; 193: 1361–71.
Muller S, Matunis MJ, Dejean A . Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J 1998; 17: 61–70.
Hayakawa F, Privalsky ML . Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. Cancer Cell 2004; 5: 389–401.
Zhu J, Lallemand-Breitenbach V, de TH . Pathways of retinoic acid- or arsenic trioxide-induced PML/RARalpha catabolism, role of oncogene degradation in disease remission. Oncogene 2001; 20: 7257–65.
Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 2004; 101: 5328–35.
Liu YF, Zhu YM, Shen SH, Shen ZX, Li JM, Chen SJ, et al. Molecular response in acute promyelocytic leukemia: a direct comparison of regular and real-time RT-PCR. Leukemia 2006; 20: 1393–9.
Zheng PZ, Wang KK, Zhang QY, Huang QH, Du YZ, Zhang QH, et al. Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci USA 2005; 102: 7653–8.
Leung J, Pang A, Yuen WH, Kwong YL, Tse EWC . Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells. Blood 2007; 109: 740–6.
Verschuus AC . Acute myeloblastic leukemia with maturation. Orphanet Encyclopedia. May 2004; http://www.orpha.net/data/patho/GB/uk-AMLM2.pdf: 1–5.
Licht JD . AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8; 21) AML. Oncogene 2001; 20: 5660–79.
Rubnitz JE, Raimondi SC, Halbert AR, Tong X, Srivastava DK, Razzouk I, et al. Characteristics and outcome of t(8; 21)-posi-tive childhood acute myeloid leukemia: a single institution's experience. Leukemia 2002; 16: 2072–7.
Peterson LF, Zhang DE . The 8; 21 translocation in leukemo-genesis. Oncogene 2004; 23: 4255–62.
Amann JM, Nip J, Strom DK, Lutterbach B, Harada H, Lenny N, et al. ETO, a target of t(8; 21) in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain. Mol Cell Biol 2001; 21: 6470–83.
Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM . ETO, fusion partner in t(8; 21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc Natl Acad Sci USA 1998; 95: 10860–5.
Uchida H, Zhang J, Nimer SD . AML1A and AML1B can transactivate the human IL-3 promoter. J Immunol 1997; 158: 2251–8.
Takahashi A, Satake M, Yamaguchi-Iwai Y, Bae SC, Lu J, Maruyama M, et al. Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2. Blood 1995; 86: 607–16.
Frank R, Zhang J, Uchida H, Meyers S, Hiebert SW, Nimer SD . The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B. Oncogene 1995; 11: 2667–74.
Klampfer L, Zhang J, Zelenetz AO, Uchida H, Nimer SD . The AML1/ETO fusion protein activates transcription of BCL-2. Proc Natl Acad Sci USA 1996; 93: 14059–64.
Shimizu K, Kitabayashi I, Kamada N, Abe T, Maseki N, Suzukawa K, et al. AML1-MTG8 leukemic protein induces the expression of granulocyte colony-stimulating factor (G-CSF) receptor through the up-regulation of CCAAT/enhancer binding protein epsilon. Blood 2000; 96: 288–96.
Higuchi M, O'Brien D, Kumaravelu P, Lenny N, Yeoh EJ, Downing JR . Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8; 21) acute myeloid leukemia. Cancer Cell 2002; 1: 63–74.
Okuda T, Cai Z, Yang S, Lenny N, Lyu CJ, van Deursen JM, et al. Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. Blood 1998; 91: 3134–43.
Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hetherington CJ, et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci USA 2001; 98: 10398–403.
Fenske TS, Pengue G, Mathews V, Hanson PT, Hamm SE, Riaz N, et al. Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice. Proc Natl Acad Sci USA 2004; 101: 15184–9.
de Guzman CG, Warren AJ, Zhang Z, Gartland L, Erickson P, Drabkin H, et al. Hematopoietic stem cell expansion and distinct myeloid developmental abnormalities in a murine model of the AML1-ETO translocation. Mol Cell Biol 2002; 22: 5506–17.
Yan M, Burel SA, Peterson LF, Kanbe E, Iwasaki H, Boyapati A, et al. From the Cover: Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development. Proc Natl Acad Sci USA 2004; 101: 17186–91.
Schessl C, Rawat VPS, Cusan M, Kanbe E, Iwasaki H, Boyapati A, et al. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J Clin Invest 2005; 115: 2159–68.
Buchholz F, Refaeli Y, Trumpp A, Bishop JM . Inducible chromosomal translocation of AML1 and ETO genes through Cre/loxP-mediated recombination in the mouse. EMBO Rep 2000; 1: 133–9.
Rhoades KL, Hetherington CJ, Harakawa N, Yergeau DA, Zhou L, Liu LQ, et al. Analysis of the role of AML1-ETO in leukemo-genesis, using an inducible transgenic mouse model. Blood 2000; 96: 2108–15.
Mulloy JC, Cammenga J, Berguido FJ, Wu K, Zhou P, Comenzo RL, et al. Maintaining the self-renewal and differentiation potential of human CD34+ hematopoietic cells using a single genetic element. Blood 2003; 102: 4369–76.
Grisolano JL, O'Neal J, Cain J, Tomasson MH . An activated receptor tyrosine kinase, TEL/PDGFbetaR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci USA 2003; 100: 9506–11.
Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322–33.
Billstrom R, Johansson B, Fioretos T, Garwicz S, Malm C, Zettervall O, et al. Poor survival in t(8; 21) (q22; q22)-associated acute myeloid leukaemia with leukocytosis. Eur J Haematol 1997; 59: 47–52.
Leblanc T, Berger R . Molecular cytogenetics of childhood acute myelogenous leukaemias. Eur J Haematol 1997; 59: 1–13.
Lee KW, Choi IS, Roh EY, Kim DY, Yun T, Lee DS, et al. Adult patients with t(8; 21) acute myeloid leukemia had no superior treatment outcome to those without t(8; 21): a single institution's experience. Ann Hematol 2004; 83: 218–24.
Matsumoto Y, Mori M, Ohtsuki T, Muroi K, Hatake K, Komatsu N, et al. Outcome of acute myelogenous leukemia in 41 patients treated with idarubicin: the prognosis of t(8; 21) cases. Rinsho Ketsueki 2001; 42: 15–22. Japanese.
Cho EK, Bang SM, Ahn JY, Yoo SM, Park PW, Seo YH, et al. Prognostic value of AML 1/ETO fusion transcripts in patients with acute myelogenous leukemia. Korean J Intern Med 2003; 18: 13–20.
Shigesada K, van de SB, Liu PP . Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11. Oncogene 2004; 23: 4297–307.
Helbling D, Mueller BU, Timchenko NA, Schardt J, Eyer M, Betts DR, et al. CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16). Blood 2005; 106: 1369–75.
Wunderlich M, Krejci O, Wei J, Mulloy JC . Human CD34+ cells expressing the inv(16) fusion protein exhibit a myelomonocytic phenotype with greatly enhanced proliferative ability. Blood 2006; 108: 1690–7.
Pession A, Martino V, Tonelli R, Kersey JH, Nakamura T, Canaani E, et al. MLL-AF9 oncogene expression affects cell growth but not terminal differentiation and is downregulated during monocyte-macrophage maturation in AML-M5 THP-1 cells. Oncogene 2003; 22: 8671–6.
Barabe F, Kennedy JA, Hope KJ, Dick JE . Modeling the initiation and progression of human acute leukemia in mice. Science 2007; 316: 600–4.
Somervaille TC, Cleary ML . Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 2006; 10: 257–68.
Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 2006; 442: 818–22.
Liu TX, Becker MW, Jelinek J, Wu WS, Deng M, Mikhalkevich N, et al. Chromosome 5q deletion and epigenetic suppression of the gene encoding [alpha]-catenin (CTNNA1) in myeloid cell transformation. Nat Med 2007; 13: 78–83.
Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446: 758–64.
Zhu YM, Zhao WL, Fu JF, Shi JY, Pan Q, Hu J, et al. NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in multifactorial leukemogenesis. Clin Cancer Res 2006; 12: 3043–9.
Chauhan D, Catley L, Li G, Podar K, Hideshima T, Velankar M, et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 2005; 8: 407–19.
Chen SJ, Wang Q, Tong JH, Xie WJ, Cao Q, Cai JR, et al. Monoallelic deletions of the P53 gene in Chinese patients with chronic myelogenous leukemia in blastic crisis. Nouv Rev Fr Hematol 1991; 33: 481–4.
Su XY, Wong N, Cao Q, Yu LZ, Niu C, Wickham N, et al. Chromosomal aberrations during progression of chronic myeloid leukemia identified by cytogenetic and molecular cyto-genetic tools: implication of 1q12-21. Cancer Genet Cytogenet 1999; 108: 6–12.
Ren R . Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 2005; 5: 172–83.
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, 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: 1031–7.
O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004.
Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–17.
Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, 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: 1038–42.
Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, et al. Imatinib induces durable hemato-logic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002; 99: 1928–37.
Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346: 645–52.
Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002; 99: 3530–9.
Yin T, Wu YL, Sun HP, Sun GL, Du YZ, Wang KK, et al. Combined effects of As4S4 and imatinib on chronic myeloid leukemia cells and BCR-ABL oncoprotein. Blood 2004; 104: 4219–25.
Du Y, Wang K, Fang H, Li J, Xiao D, Zheng P, et al. Coordination of intrinsic, extrinsic, and endoplasmic reticulum-mediated apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid leukemia. Blood 2006; 107: 1582–90.
Chiorazzi N, Rai KR, Ferrarini M . Chronic lymphocytic leukemia. N Engl J Med 2005; 352: 804–15.
Hallek M . Chronic lymphocytic leukemia (CLL): First-line treatment. Hematology Am Soc Hematol Edu Program 2005; 285–91.
Raval A, Tanner SM, Byrd JC, Angerman EB, Perko JD, Chen SS, et al. Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 2007; 129: 879–90.
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2002; 99: 15524–9.
Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci USA 2004; 101: 11755–60.
Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005; 353: 1793–801.
Mecucci C, Rosati R, Starza RL . Genetic profile of acute myeloid leukemia. Rev Clin Exp Hematol 2002; 6: 3–25.
Hu J, Zhou GB, Wang ZY, Chen SJ, Chen Z . Mutant transcription factors and tyrosine kinases as therapeutic targets for leukemias: from acute promyelocytic leukemia to chronic myeloid leukemia and beyond. Adv Cancer Res 2007; 98: 191–220.
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Zhou, Gb., Li, G., Chen, Sj. et al. From dissection of disease pathogenesis to elucidation of mechanisms of targeted therapies: leukemia research in the genomic era. Acta Pharmacol Sin 28, 1434–1449 (2007). https://doi.org/10.1111/j.1745-7254.2007.00684.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00684.x
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