The molecular analysis of recurring chromosome rearrangements, especially of translocations and inversions, has provided us with valuable insight into the pathogenesis of hematological malignancies. Many translocations result in the fusion of genes located at the translocation breakpoints. In recent years we have witnessed a rapid rise in the number of chromosome translocations in leukemias being characterized at the molecular level. However, the number of genes being newly identified as translocation fusion genes has not risen at the same pace. This is due to the fact that several genes are involved in more than one translocation forming fusion genes with a number of other partner genes. Not only does one find star-shaped topologies, with one gene forming fusions with several others (e.g. ETV6/PDGFRB, ETV6/JAK2, ETV6/ABL etc.), but also networks connecting several genes with more than one fusion partner (e.g. ETV6/RUNX1 (AML1), RUNX1/CBFA2T1 (ETO), ETV6/EVI1, RUNX1/EVI1, ETV6/ABL, BCR/ABL). The emergence of such networks with the “recycling” of genes in new fusion combinations suggests that there is a rather limited number of genes which can be altered to cause leukemia.   

1.
Bannister AJ, Kouzarides T: The CBP co-activator is a histone acetyltransferase. Nature 384:641–643 (1996).
2.
Bohlander SK, Muschinsky V, Schrader K, Siebert R, Schlegelberger B, Harder L, Schemmel V, Fonatsch C, Ludwig W-D, Hiddemann W, Dreyling MH: Molecular analysis of the CALM/AF10 fusion: Identical rearrangements in acute myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma patients. Leukemia 14:93–99 (2000).
3.
Borrow J, Stanton VJ, Andresen JM, Becher R, Behm FG, Chaganti RS, Civin CI, Disteche C, Dube I, Frischauf AM, Horsman D, Mitelman F, Volinia S, Watmore AE, Housman DE: The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nature Genet 14:33–41 (1996).
4.
Buijs A, Sherr S, van Baal S, van Bezouw S, van der Plas D, Geurts van Kessel A, Riegman P, Lekanne Deprez R, Zwarthoff E, Hagemeijer A, Grosveld G: Translocation (12;22)(p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11. Oncogene 10:1511–1519 (1995).
5.
Caligiuri MA, Strout MP, Schichman SA, Mrózek K, Arthur DC, Herzig GP, Baer MR, Schiffer CA, Heinonen K, Knuutila S, Nousiainen T, Ruutu T, Block AW, Schulman P, Pedersen BJ, Croce CM, Bloomfield CD: Partial tandem duplication of ALL1 as a recurrent molecular defect in acute myeloid leukemia with trisomy 11. Cancer Res 56:1418–1425 (1996).
6.
Carapeti M, Aguiar RC, Goldman JM, Cross NC: A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia. Blood 91:3127–3133 (1998).
7.
Cazzaniga G, Tosi S, Aloisi A, Giudici G, Daniotti M, Pioltelli P, Kearney L, Biondi A: The tyrosine kinase Abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): Molecular cloning of both reciprocal transcripts. Blood 94:4370–4373 (1999).
8.
Champagne N, Bertos NR, Pelletier N, Wang AH, Vezmar M, Yang Y, Heng HH, Yang X-J: Identification of a human histone acetyltransferase related to monocytic leukemia zinc finger protein. J biol Chem 274:28528–28536 (1999).
9.
Chaplin T, Ayton P, Bernard OA, Saha V, Della Valle V, Hillion J, Gregorini A, Lillington D, Berger R, Young BD: A novel class of zinc finger/leucine zipper genes identified from the molecular cloning of the t(10;11) translocation in acute leukemia. Blood 85:1435–1441 (1995).
10.
Chase A, Reiter A, Burci L, Cazzaniga G, Biondi A, Pickard J, Roberts IA, Goldman JM, Cross NC: Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). Blood 93:1025–1031 (1999).
11.
Cools J, Bilhou NC, Wlodarska I, Cabrol C, Talmant P, Bernard P, Hagemeijer A, Marynen P: Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q12;p13). Blood 94:1820–1824 (1999).
12.
Dreyling MH, Martinez-Climent JA, Zheng M, Mao J, Rowley JD, Bohlander SK: The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3-clathrin assembly protein family. Proc natl Acad Sci, USA 93:4804–4809 (1996).
13.
Eguchi M, Eguchi IM, Tojo A, Morishita K, Suzuki K, Sato Y, Kudoh S, Tanaka K, Setoyama M, Nagamura F, Asano S, Kamada N: Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25). Blood 93:1355–1363 (1999).
14.
Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Bray-Ward P, Morgan E, Raimondi SC, Rowley JD, Gilliland DG: Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc natl Acad Sci, USA 92:4917–4921 (1995).
15.
Golub TR, Barker GF, Lovett M, Gilliland DG: Fusion of PDGF receptor β to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 77:307–316 (1994).
16.
Golub TR, Goga A, Barker GF, Afar DE, McLaughlin J, Bohlander SK, Rowley JD, Witte ON, Gilliland DG: Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. Mol Cell Biol 16:4107–4116 (1996).
17.
Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M, Schudy A: The DNA sequence of human chromosome 21. Nature 405:311–319 (2000).
18.
Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J: Acute leukaemia in bcr/abl transgenic mice. Nature 344:251–253 (1990).
19.
Heisterkamp N, Stam K, Groffen J, de Klein A, Grosveld G: Structural organization of the bcr gene and its role in the Ph1 translocation. Nature 315:758–761 (1985).
20.
Heisterkamp N, Stephenson J, Groffen J, Hansen P, de Klein A, Bartram C, Grosveld G: Localization of the c-abl oncogene adjacent to a translocation breakpoint in chronic myelocytic leukemia. Nature 306:239–242 (1983).
21.
Hilfiker A, Hilfiker KD, Pannuti A, Lucchesi JC: mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila. EMBO J 16:2054–2060 (1997).
22.
Huettner CS, Zhang P, Van Etten RA, Tenen DG: Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nature Genet 24:57–60 (2000).
23.
Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto M, Ohki M, Hayashi Y: Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13). Blood 90:4699–4704 (1997).
24.
Iijima Y, Ito T, Oikawa T, Eguchi M, Eguchi-Ishimae M, Kamada N, Kishi K, Asano S, Sakaki Y, Sato Y: A new ETV6/TEL partner gene, ARG (ABL related gene or ABL2), identified in an AML-M3 cell line with a t(1;12)(q25;p13) translocation. Blood 95:2126–2131 (2000).
25.
Kamine J, Elangovan B, Subramanian T, Coleman D, Chinnadurai G: Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator. Virology 216:357–66 (1996).
26.
Kimura A, Horikoshi M: Tip60 acetylates six lysines of a specific class in core histones in vitro. Genes Cells 3:789–800 (1998).
27.
Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH: A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nature Genet 18:184–187 (1998).
28.
Kobayashi H, Montgomery KT, Bohlander SK, Adra CN, Lim BL, Kucherlapati RS, Donis-Keller H, Holt MS, Le Beau MM, Rowley JD: Fluorescence in situ hybridization mapping of translocations and deletions involving the short arm of human chromosome 12 in malignant hematologic diseases. Blood 84:3473–3482 (1994).
29.
Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffe M, Berthou C, Lessard M, Berger R, Ghysdael J, Bernard OA: A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 278:1309–1312 (1997).
30.
Lekanne Deprez RH, Riegman PH, Groen NA, Warringa UL, van Biezen NA, Molijn AC, Bootsma D, de Jong PJ, Menon AG, Kley NA, et al: Cloning and characterization of MN1, a gene from chromosome 22q11, which is disrupted by a balanced translocation in a meningioma. Oncogene 10:1521–1528 (1995).
31.
Leo C, Chen JD: The SRC family of nuclear receptor coactivators. Gene 245:1–11 (2000).
32.
Liang J, Prouty L, Williams BJ, Dayton MA, Blanchard KL: Acute mixed lineage leukemia with an inv(8)(p11q13) resulting in fusion of the genes for MOZ and TIF2. Blood 92:2118–2122 (1998).
33.
Liu P, Tarle SA, Hajra A, Claxton DF, Marlton P, Freedman M, Siciliano MJ, Collins FS: Fusion between transcription factor CBFβ/PEBP2β and a myosin heavy chain in acute myeloid leukemia. Science 261:1041 (1993).
34.
Mitelman F: Catalog of Chromosome Aberrations in Cancer. (Alan R. Liss, New York 1994).
35.
Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y, Ohki M: t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc natl Acad Sci, USA 88:10431–10434 (1991).
36.
Mrózek K, Heinonen K, de la Chalpelle A, Bloomfield CD: Clinical significance of cytogenetics in acute myeloid leukemia. Semin Oncol 24:17–31 (1997).
37.
Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, Fujimoto T, Misawa S: Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 10:1911–1918 (1996).
38.
Nowell PC, Hungerford DA: A minute chromosome in human granulocytic leukemia. Science 132:1497 (1960).
39.
Nucifora G, Rowley JD: AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Blood 86:1–14 (1995).
40.
Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y: The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87:953–959 (1996).
41.
Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR: AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84:321–330 (1996).
42.
Papadopoulos P, Ridge SA, Boucher CA, Stocking C, Wiedemann LM: The novel activation of ABL by fusion to an ets-related gene, TEL. Cancer Res 55:34–38 (1995).
43.
Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, Monpoux F, Van Rompaey L, Baens M, Van den Berghe H, Marynen P: Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor- associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood 90:2535–2540 (1997a).
44.
Peeters P, Wlodarska I, Baens M, Criel A, Selleslag D, Hagemeijer A, Van den Berghe H, Marynen P: Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders. Cancer Res 57:564–569 (1997b).
45.
Reifsnyder C, Lowell J, Clarke A, Pillus L: Yeast SAS silencing genes and human genes associated with AML and HIV-1 Tat interactions are homologous with acetyltransferases. Nature Genet 14:42–49 (1996).
46.
Romana SP, Le Coniat M, Poirel H, Marynen P, Bernard OA, Berger R: Deletion of the short arm of chromosome 12 is a secondary event in acute lymphoblastic leukemia with t(12;21). Leukemia 10:167–170 (1996).
47.
Ross TS, Bernard OA, Berger R, Gilliland DG: Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7) (q33;q11.2). Blood 91:4419–4426 (1998).
48.
Rowley J: A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature 243:290–293 (1973).
49.
Rowley JD: Recurring chromosome abnormalities in leukemia and lymphoma. Semin Hematol 27:122–136 (1990).
50.
Rubin BP, Chen CJ, Morgan TW, Xiao S, Grier HE, Kozakewich HP, Perez AA, Fletcher JA: Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. Am J Pathol 153:1451–8 (1998).
51.
Rubnitz JE, Behm FG, Downing JR: 11q23 rearrangements in acute leukemia. Leukemia 10:74–82 (1996).
52.
Shtivelman E, Lifshitz B, Gale R, Canaani E: Fused transcript of Abl and Bcr genes in chronic myelogenous leukemia. Nature 315:550–554 (1985).
53.
Shurtleff SA, Buijs A, Behm FG, Rubnitz JE, Raimondi SC, Hancock ML, Chan GC-F, Pui C-H, Grosveld G, Downing JR: Tel/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia 9:1985–1989 (1995).
54.
Sobulo OM, Borrow J, Tomek R, Reshmi S, Harden A, Schlegelberger B, Housman D, Doggett NA, Rowley JD, Zeleznik-Le NJ: MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3). Proc natl Acad Sci, USA 94:8732–8737 (1997).
55.
Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, Ratajczak J, Resende IC, Haworth C, Hock R, Loh M, Felix C, Roy DC, Busque L, Kurnit D, Willman C, Gewirtz AM, Speck NA, Bushweller JH, Li FP, Gardiner K, Poncz M, Maris JM, Gilliland DG: Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nature Genet 23:166–175 (1999).
56.
Suto Y, Sato Y, Smith SD, Rowley JD, Bohlander SK: A t(6;12)(q23;p13) results in the fusion of ETV6 to a novel gene, STL, in a B-cell ALL cell line. Genes Chrom Cancer 18:254–268 (1997).
57.
Taki T, Sako M, Tsuchida M, Hayashi Y: The t(11;16)(q23;p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene. Blood 89:3945–3950 (1997).
58.
Taub R, Kirsch I, Morton C, Lenoir G, Swam D, Aaronson S, Leder P: Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc natl Acad Sci, USA 79:7837–7841 (1982).
59.
Thirman MJ, Gill HJ, Burnett RC, Mbangkollo D, McCabe NR, Kobayashi H, Ziemin-van der Poel S, Kaneko Y, Morgan R, Sandberg AA, Chaganti RSK, Larson RA, Le Beau MM, Diaz MO, Rowley JD: Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations. New Engl J Med 329:909–914 (1993).
60.
Voegel JJ, Heine MJ, Tini M, Vivat V, Chambon P, Gronemeyer H: The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J 17:507–519 (1998).
61.
Wang LC, Kuo F, Fujiwara Y, Gilliland DG, Golub TR, Orkin SH: Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL. Embo J 16: 4374–4383 (1997).
62.
Wang LC, Swat W, Fujiwara Y, Davidson L, Visvader J, Kuo F, Alt FW, Gilliland DG, Golub TR, Orkin SH: The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow. Genes Dev 12:2392–2402 (1998).
63.
Yagasaki F, Jinnai I, Yoshida S, Yokoyama Y, Matsuda A, Kusumoto S, Kobayashi H, Terasaki H, Ohyashiki K, Asou N, Murohashi I, Bessho M, Hirashima K: Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13). Genes Chrom Cancer 26:192-202 (1999).
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