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Molecular analysis of more than 140 gene fusion variants and aberrant activation of EVI1 and TLX1 in hematological malignancies

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Abstract

Gene fusions are observed in abnormal chromosomal rearrangements such as translocations in hematopoietic malignancies, especially leukemia subtypes. Hence, it is critical to obtain correct information about these rearrangements in order to apply proper treatment techniques. To identify abnormal molecular changes in patients with leukemia, we developed a multiplex reverse transcriptase polymerase chain reaction (MRT-PCR) protocol and investigated more than 140 gene fusions resulting from variations of 29 prevalent chromosomal rearrangements along with EVI1 and TLX1 oncogenic expression in the presence of optimized primers. The potential of the MRT-PCR method was approved by evaluating the available cell lines as positive control and confirmed by sequencing. Samples from 53 patients afflicted with hematopoiesis malignancies were analyzed. Results revealed at least one chromosomal rearrangement in 69% of acute myeloid leukemia subjects, 64% of acute lymphoblastic leukemia subjects, and 81% of chronic myeloid leukemia subjects, as well as a subject with hypereosinophilic syndrome. Also, five novel fusion variants were detected. Results of this study also showed that chromosomal rearrangements, both alone and in conjunction with other rearrangements, are involved in leukemogenesis. Moreover, it was found that EVI1 is a suitable hallmark for hematopoietic malignancies.

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Reference

  1. Bacolla A, Tainer JA, Vasquez KM, Cooper DN (2016) Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences. Nucleic Acids Res 44(12):5673–5688. doi:10.1093/nar/gkw261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nambiar M, Raghavan SC (2011) How does DNA break during chromosomal translocations? Nucleic Acids Res 39(14):5813–5825. doi:10.1093/nar/gkr223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pallisgaard N, Hokland P, Riishoj DC, Pedersen B, Jorgensen P (1998) Multiplex reverse transcription-polymerase chain reaction for simultaneous screening of 29 translocations and chromosomal aberrations in acute leukemia. Blood 92(2):574–588

    CAS  PubMed  Google Scholar 

  4. Liu PP, Hajra A, Wijmenga C, Collins FS (1995) Molecular pathogenesis of the chromosome 16 inversion in the M4Eo subtype of acute myeloid leukemia. Blood 85(9):2289–2302

    CAS  PubMed  Google Scholar 

  5. Pandolfi PP, Alcalay M, Fagioli M, Zangrilli D, Mencarelli A, Diverio D, Biondi A, Lo Coco F, Rambaldi A, Grignani F et al (1992) Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia. EMBO J 11(4):1397–1407

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Meyer-Monard S, Parlier V, Passweg J, Muhlematter D, Hess U, Bargetzi M, Kuhne T, Cabrol C, Gratwohl A, Jotterand M, Tichelli A (2006) Combination of broad molecular screening and cytogenetic analysis for genetic risk assignment and diagnosis in patients with acute leukemia. Leukemia 20(2):247–253. doi:10.1038/sj.leu.2404044

    Article  CAS  PubMed  Google Scholar 

  7. Bonomi R, Giordano H, del Pilar MM, Bodega E, Landoni AI, Gallagher R, del Rosario UM (2000) Simultaneous PML/RARalpha and AML1/ETO expression with t(15;17) at onset and relapse with only t(8;21) in an acute promyelocytic leukemia patient. Cancer Genet Cytogenet 123(1):41–43

    Article  CAS  PubMed  Google Scholar 

  8. Berger R, Bernheim A, Daniel MT, Flandrin G (1983) t(15;17) in a promyelocytic form of chronic myeloid leukemia blastic crisis. Cancer Genet Cytogenet 8(2):149–152

    Article  CAS  PubMed  Google Scholar 

  9. Licht JD (2001) AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8;21) AML. Oncogene 20(40):5660–5679. doi:10.1038/sj.onc.1204593

    Article  CAS  PubMed  Google Scholar 

  10. Elia L, Mancini M, Moleti L, Meloni G, Buffolino S, Krampera M, De Rossi G, Foa R, Cimino G (2003) A multiplex reverse transcriptase-polymerase chain reaction strategy for the diagnostic molecular screening of chimeric genes: a clinical evaluation on 170 patients with acute lymphoblastic leukemia. Haematologica 88(3):275–279

    CAS  PubMed  Google Scholar 

  11. Geng Z, Zhang H, Wang D, Xiao Y, Wang N, Li C, Huang L, Zhou J (2012) Combination of cytogenetic analysis and molecular screening in patients with de novo acute myeloid leukemia. J Huazhong Univ Sci Technolog Med Sci 32(4):501–510. doi:10.1007/s11596-012-0087-6

    Article  CAS  PubMed  Google Scholar 

  12. Pruett SB, Obiri N, Kiel JL (1989) Involvement and relative importance of at least two distinct mechanisms in the effects of 2-mercaptoethanol on murine lymphocytes in culture. J Cell Physiol 141(1):40–45. doi:10.1002/jcp.1041410107

    Article  CAS  PubMed  Google Scholar 

  13. De Weer A, Poppe B, Cauwelier B, Van Roy N, Dastugue N, Hagemeijer A, De Paepe A, Speleman F (2006) Screening for EVI1: ectopic expression absent in T-cell acute lymphoblastic leukemia patients and cell lines. Cancer Genet Cytogenet 171(1):79–80. doi:10.1016/j.cancergencyto.2006.07.004

    Article  PubMed  Google Scholar 

  14. Sato T, Goyama S, Kataoka K, Nasu R, Tsuruta-Kishino T, Kagoya Y, Nukina A, Kumagai K, Kubota N, Nakagawa M, Arai S, Yoshimi A, Honda H, Kadowaki T, Kurokawa M (2014) Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Oncogene 33(42):5028–5038. doi:10.1038/onc.2014.108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Raza A, Buonamici S, Lisak L, Tahir S, Li D, Imran M, Chaudary NI, Pervaiz H, Gallegos JA, Alvi MI, Mumtaz M, Gezer S, Venugopal P, Reddy P, Galili N, Candoni A, Singer J, Nucifora G (2004) Arsenic trioxide and thalidomide combination produces multi-lineage hematological responses in myelodysplastic syndromes patients, particularly in those with high pre-therapy EVI1 expression. Leuk Res 28(8):791–803. doi:10.1016/j.leukres.2003.11.018

    Article  CAS  PubMed  Google Scholar 

  16. Smol T, Nibourel O, Marceau-Renaut A, Celli-Lebras K, Berthon C, Quesnel B, Boissel N, Terre C, Thomas X, Castaigne S, Dombret H, Preudhomme C, Renneville A (2015) Quantification of EVI1 transcript levels in acute myeloid leukemia by RT-qPCR analysis: a study by the ALFA Group. Leuk Res 39(12):1443–1447. doi:10.1016/j.leukres.2015.09.021

    Article  CAS  PubMed  Google Scholar 

  17. Stevens A, Hanson D, de Leonibus C, Whatmore A, Donn R, White DJ, Liu J, van den Heuvel-Eibrink MM, Saha V, Clayton PE, Meyer S (2014) EVI1 expression in childhood acute lymphoblastic leukaemia is not restricted to MLL and BCR/ABL rearrangements and is influenced by age. Blood Cancer J 4:e179. doi:10.1038/bcj.2013.76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kennedy MA, Gonzalez-Sarmiento R, Kees UR, Lampert F, Dear N, Boehm T, Rabbitts TH (1991) HOX11, a homeobox-containing T-cell oncogene on human chromosome 10q24. Proc Natl Acad Sci U S A 88(20):8900–8904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Aplan PD, Lombardi DP, Ginsberg AM, Cossman J, Bertness VL, Kirsch IR (1990) Disruption of the human SCL locus by “illegitimate” V-(D)-J recombinase activity. Science 250(4986):1426–1429

    Article  CAS  PubMed  Google Scholar 

  20. Caligiuri MA, Strout MP, Schichman SA, Mrozek K, Arthur DC, Herzig GP, Baer MR, Schiffer CA, Heinonen K, Knuutila S, Nousiainen T, Ruutu T, Block AW, Schulman P, Pedersen-Bjergaard J, Croce CM, Bloomfield CD (1996) Partial tandem duplication of ALL1 as a recurrent molecular defect in acute myeloid leukemia with trisomy 11. Cancer Res 56(6):1418–1425

    CAS  PubMed  Google Scholar 

  21. Poirel H, Rack K, Delabesse E, Radford-Weiss I, Troussard X, Debert C, Leboeuf D, Bastard C, Picard F, Veil-Buzyn A, Flandrin G, Bernard O, Macintyre E (1996) Incidence and characterization of MLL gene (11q23) rearrangements in acute myeloid leukemia M1 and M5. Blood 87(6):2496–2505

    CAS  PubMed  Google Scholar 

  22. van der Reijden BA, Dauwerse HG, Giles RH, Jagmohan-Changur S, Wijmenga C, Liu PP, Smit B, Wessels HW, Beverstock GC, Jotterand-Bellomo M, Martinet D, Muhlematter D, Lafage-Pochitaloff M, Gabert J, Reiffers J, Bilhou-Nabera C, van Ommen GJ, Hagemeijer A, Breuning MH (1999) Genomic acute myeloid leukemia-associated inv(16)(p13q22) breakpoints are tightly clustered. Oncogene 18(2):543–550. doi:10.1038/sj.onc.1202321

    Article  PubMed  Google Scholar 

  23. Stulberg J, Kamel-Reid S, Chun K, Tokunaga J, Wells RA (2002) Molecular analysis of a new variant of the CBF beta-MYH11 gene fusion. Leuk Lymphoma 43(10):2021–2026. doi:10.1080/1042819021000015989-1

    Article  CAS  PubMed  Google Scholar 

  24. Rowe D, Strain L, Lowe C, Jones G (2007) A case of acute myeloid leukemia with inv(16)(p13q22) reveals a novel MYH11 breakpoint and a new CBF beta-MYH11 transcript variant. Haematologica 92(10):1433–1434. doi:10.3324/haematol.11536

    Article  CAS  PubMed  Google Scholar 

  25. Borkhardt A, Repp R, Haas OA, Leis T, Harbott J, Kreuder J, Hammermann J, Henn T, Lampert F (1997) Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Oncogene 14(2):195–202. doi:10.1038/sj.onc.1200814

    Article  CAS  PubMed  Google Scholar 

  26. Tse W, Zhu W, Chen HS, Cohen A (1995) A novel gene, AF1q, fused to MLL in t(1;11) (q21;q23), is specifically expressed in leukemic and immature hematopoietic cells. Blood 85(3):650–656

    CAS  PubMed  Google Scholar 

  27. Busson-Le Coniat M, Salomon-Nguyen F, Hillion J, Bernard OA, Berger R (1999) MLL-AF1q fusion resulting from t(1;11) in acute leukemia. Leukemia 13(2):302–306

    Article  CAS  PubMed  Google Scholar 

  28. Lee SG, Park TS, Yang JJ, Oh SH, Cho EH, Lee S, Oh D, Huh JY, Marschalek R, Meyer C (2012) Molecular identification of a new splicing variant of the MLL - MLLT11 fusion transcript in an adult with acute myeloid leukemia and t(1;11)(q21;q23). Acta Haematol 128(3):131–138. doi:10.1159/000338258

    Article  CAS  PubMed  Google Scholar 

  29. Sagawa M, Shimizu T, Shimizu T, Awaya N, Mitsuhashi T, Ikeda Y, Okamoto S, Kizaki M (2006) Establishment of a new human acute monocytic leukemia cell line TZ-1 with t(1;11)(p32;q23) and fusion gene MLL-EPS15. Leukemia 20(9):1566–1571. doi:10.1038/sj.leu.2404305

    Article  CAS  PubMed  Google Scholar 

  30. Bernard OA, Mauchauffe M, Mecucci C, Van den Berghe H, Berger R (1994) A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-4, AF-9 nor ENL. Oncogene 9(4):1039–1045

    CAS  PubMed  Google Scholar 

  31. Nourse J, Mellentin JD, Galili N, Wilkinson J, Stanbridge E, Smith SD, Cleary ML (1990) Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 60(4):535–545

    Article  CAS  PubMed  Google Scholar 

  32. Izraeli S, Kovar H, Gadner H, Lion T (1992) Unexpected heterogeneity in E2A/PBX1 fusion messenger RNA detected by the polymerase chain reaction in pediatric patients with acute lymphoblastic leukemia. Blood 80(6):1413–1417

    CAS  PubMed  Google Scholar 

  33. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT (1994) Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263(5151):1281–1284

    Article  CAS  PubMed  Google Scholar 

  34. Trumper L, Daus H, Merz H, von Bonin F, Loftin U, Cochlovius C, Moller P, Feller AC, Pfreundschuh M (1997) NPM/ALK fusion mRNA expression in Hodgkin and Reed-Sternberg cells is rare but does occur: results from single-cell cDNA analysis. Ann Oncol 8(Suppl 2):83–87

    Article  PubMed  Google Scholar 

  35. Weisenburger DD, Gordon BG, Vose JM, Bast MA, Chan WC, Greiner TC, Anderson JR, Sanger WG (1996) Occurrence of the t(2;5)(p23;q35) in non-Hodgkin's lymphoma. Blood 87(9):3860–3868

    CAS  PubMed  Google Scholar 

  36. Yoneda-Kato N, Look AT, Kirstein MN, Valentine MB, Raimondi SC, Cohen KJ, Carroll AJ, Morris SW (1996) The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 12(2):265–275

    CAS  PubMed  Google Scholar 

  37. Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H, Yazaki Y, Ohki M, Hirai H (1994) Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia. EMBO J 13(3):504–510

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Nucifora G, Begy CR, Kobayashi H, Roulston D, Claxton D, Pedersen-Bjergaard J, Parganas E, Ihle JN, Rowley JD (1994) Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations. Proc Natl Acad Sci U S A 91(9):4004–4008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yamamoto K, Seto M, Iida S, Komatsu H, Kamada N, Kojima S, Kodera Y, Nakazawa S, Saito H, Takahashi T et al (1994) A reverse transcriptase-polymerase chain reaction detects heterogeneous chimeric mRNAs in leukemias with 11q23 abnormalities. Blood 83(10):2912–2921

    CAS  PubMed  Google Scholar 

  40. Downing JR, Head DR, Raimondi SC, Carroll AJ, Curcio-Brint AM, Motroni TA, Hulshof MG, Pullen DJ, Domer PH (1994) The der(11)-encoded MLL/AF-4 fusion transcript is consistently detected in t(4;11)(q21;q23)-containing acute lymphoblastic leukemia. Blood 83(2):330–335

    CAS  PubMed  Google Scholar 

  41. Ivanov IC, Jitaru D, Grigore GE, Zlei M, Ivanov AV, Dumitras S, Carasevici E, Miron IC (2013) Infant acute leukemia with lineage switch at relapse expressing a novel t(4;11)(q21;q23) MLL-AF4 fusion transcript. Revista Româd de Medicin de Laborator 21:47–58. doi:10.2478/rrlm-2013-0017

    Google Scholar 

  42. Corral J, Forster A, Thompson S, Lampert F, Kaneko Y, Slater R, Kroes WG, van der Schoot CE, Ludwig WD, Karpas A et al (1993) Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation. Proc Natl Acad Sci U S A 90(18):8538–8542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Abdelhaleem M, Yi Q, Beimnet K, Grant R (2007) A novel t(4;11)(q21;q23) MLL-AF4 fusion transcript in infant leukemia. Am J Hematol 82(3):247. doi:10.1002/ajh.20731

    Article  PubMed  Google Scholar 

  44. Curtis CE, Grand FH, Waghorn K, Sahoo TP, George J, Cross NC (2007) A novel ETV6-PDGFRB fusion transcript missed by standard screening in a patient with an imatinib responsive chronic myeloproliferative disease. Leukemia 21(8):1839–1841. doi:10.1038/sj.leu.2404728

    Article  CAS  PubMed  Google Scholar 

  45. Golub TR, Barker GF, Lovett M, Gilliland DG (1994) Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 77(2):307–316

    Article  CAS  PubMed  Google Scholar 

  46. Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ (1996) The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 87(3):882–886

    CAS  PubMed  Google Scholar 

  47. Hamaguchi H, Nagata K, Yamamoto K, Fujikawa I, Kobayashi M, Eguchi M (1998) Establishment of a novel human myeloid leukaemia cell line (FKH-1) with t(6;9)(p23;q34) and the expression of dek-can chimaeric transcript. Br J Haematol 102(5):1249–1256

    Article  CAS  PubMed  Google Scholar 

  48. Chen S, Xue Y, Zhang X, Wu Y, Pan J, Wang Y, Ceng J (2005) A new human acute monocytic leukemia cell line SHI-1 with t(6;11)(q27;q23), p53 gene alterations and high tumorigenicity in nude mice. Haematologica 90(6):766–775

    CAS  PubMed  Google Scholar 

  49. Kakuda H, Sato T, Hayashi Y, Enomoto Y, Takayama J, Ohira M, Seto M, Ueda R, Fuse A, Niimi H (1996) A novel human leukaemic cell line, CTS, has a t(6;11) chromosomal translocation and characteristics of pluripotent stem cells. Br J Haematol 95(2):306–318

    Article  CAS  PubMed  Google Scholar 

  50. Miyoshi H, Kozu T, Shimizu K, Enomoto K, Maseki N, Kaneko Y, Kamada N, Ohki M (1993) The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. EMBO J 12(7):2715–2721

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Matozaki S, Nakagawa T, Kawaguchi R, Aozaki R, Tsutsumi M, Murayama T, Koizumi T, Nishimura R, Isobe T, Chihara K (1995) Establishment of a myeloid leukaemic cell line (SKNO-1) from a patient with t(8;21) who acquired monosomy 17 during disease progression. Br J Haematol 89(4):805–811

    Article  CAS  PubMed  Google Scholar 

  52. Quentmeier H, Schneider B, Rohrs S, Romani J, Zaborski M, Macleod RA, Drexler HG (2009) SET-NUP214 fusion in acute myeloid leukemia- and T-cell acute lymphoblastic leukemia-derived cell lines. J Hematol Oncol 2:3. doi:10.1186/1756-8722-2-3

    Article  PubMed  PubMed Central  Google Scholar 

  53. Van Vlierberghe P, van Grotel M, Tchinda J, Lee C, Beverloo HB, van der Spek PJ, Stubbs A, Cools J, Nagata K, Fornerod M, Buijs-Gladdines J, Horstmann M, van Wering ER, Soulier J, Pieters R, Meijerink JP (2008) The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. Blood 111(9):4668–4680. doi:10.1182/blood-2007-09-111872

    Article  PubMed  PubMed Central  Google Scholar 

  54. Rosati R, La Starza R, Barba G, Gorello P, Pierini V, Matteucci C, Roti G, Crescenzi B, Aloisi T, Aversa F, Martelli MF, Mecucci C (2007) Cryptic chromosome 9q34 deletion generates TAF-Ialpha/CAN and TAF-Ibeta/CAN fusion transcripts in acute myeloid leukemia. Haematologica 92(2):232–235

    Article  CAS  PubMed  Google Scholar 

  55. Pession A, Martino V, Tonelli R, Beltramini C, Locatelli F, Biserni G, Franzoni M, Freccero F, Montemurro L, Pattacini L, Paolucci G (2003) 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 22(54):8671–8676. doi:10.1038/sj.onc.1207125

    Article  CAS  PubMed  Google Scholar 

  56. Montemurro L, Tonelli R, Fazzina R, Martino V, Marino F, Pession A (2004) Identification of two MLL-MLLT3 (alias MLL-AF9) chimeric transcripts in the MOLM-13 cell line. Cancer Genet Cytogenet 154(1):96–97. doi:10.1016/j.cancergencyto.2004.01.029

    Article  CAS  PubMed  Google Scholar 

  57. Alonso CN, Longo PL, Gallego MS, Medina A, Felice MS (2008) A novel AF9 breakpoint in MLL-AF9-positive acute monoblastic leukemia. Pediatr Blood Cancer 50(4):869–871. doi:10.1002/pbc.21393

    Article  PubMed  Google Scholar 

  58. Nakamura T, Alder H, Gu Y, Prasad R, Canaani O, Kamada N, Gale RP, Lange B, Crist WM, Nowell PC et al (1993) Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs. Proc Natl Acad Sci U S A 90(10):4631–4635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mitterbauer G, Zimmer C, Fonatsch C, Haas O, Thalhammer-Scherrer R, Schwarzinger I, Kalhs P, Jaeger U, Lechner K, Mannhalter C (1999) Monitoring of minimal residual leukemia in patients with MLL-AF9 positive acute myeloid leukemia by RT-PCR. Leukemia 13(10):1519–1524

    Article  CAS  PubMed  Google Scholar 

  60. Baeumler J, Szuhai K, Falkenburg JH, van Schie ML, Ottmann OG, Nijmeijer BA (2008) Establishment and cytogenetic characterization of a human acute lymphoblastic leukemia cell line (ALL-VG) with ETV6/ABL1 rearrangement. Cancer Genet Cytogenet 185(1):37–42. doi:10.1016/j.cancergencyto.2008.05.001

    Article  CAS  PubMed  Google Scholar 

  61. Park J, Kim M, Lim J, Kim Y, Han K, Kim JS, Lee S, Kim HJ, Min WS (2013) Variant of ETV6/ABL1 gene is associated with leukemia phenotype. Acta Haematol 129(2):78–82. doi:10.1159/000342490

    Article  CAS  PubMed  Google Scholar 

  62. Gancheva K, Virchis A, Howard-Reeves J, Cross NC, Brazma D, Grace C, Kotzampaltiris P, Partheniou F, Nacheva E (2013) Myeloproliferative neoplasm with ETV6-ABL1 fusion: a case report and literature review. Mol Cytogenet 6(1):39. doi:10.1186/1755-8166-6-39

    Article  PubMed  PubMed Central  Google Scholar 

  63. Yamamoto K, Yakushijin K, Nakamachi Y, Miyata Y, Sanada Y, Tanaka Y, Okamura A, Kawano S, Hayashi Y, Matsuoka H, Minami H (2014) Extramedullary T-lymphoid blast crisis of an ETV6/ABL1-positive myeloproliferative neoplasm with t(9;12)(q34;p13) and t(7;14)(p13;q11.2). Ann Hematol 93(8):1435–1438. doi:10.1007/s00277-013-1975-y

    Article  PubMed  Google Scholar 

  64. Matsuo Y, Drexler HG, Takeuchi M, Orita K (1999) A novel biphenotypic B-cell precursor leukemia cell line (NALM-29) carrying t(9;22)(q34;q11) established from a patient with acute leukemia. Leuk Res 23(8):731–740

    Article  CAS  PubMed  Google Scholar 

  65. Hermans A, Heisterkamp N, von Linden M, van Baal S, Meijer D, van der Plas D, Wiedemann LM, Groffen J, Bootsma D, Grosveld G (1987) Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia. Cell 51(1):33–40

    Article  CAS  PubMed  Google Scholar 

  66. Chaplin T, Bernard O, Beverloo HB, Saha V, Hagemeijer A, Berger R, Young BD (1995) The t(10;11) translocation in acute myeloid leukemia (M5) consistently fuses the leucine zipper motif of AF10 onto the HRX gene. Blood 86(6):2073–2076

    CAS  PubMed  Google Scholar 

  67. Prasad R, Leshkowitz D, Gu Y, Alder H, Nakamura T, Saito H, Huebner K, Berger R, Croce CM, Canaani E (1994) Leucine-zipper dimerization motif encoded by the AF17 gene fused to ALL-1 (MLL) in acute leukemia. Proc Natl Acad Sci U S A 91(17):8107–8111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Strehl S, Konig M, Meyer C, Schneider B, Harbott J, Jager U, von Bergh AR, Loncarevic IF, Jarosova M, Schmidt HH, Moore SD, Marschalek R, Haas OA (2006) Molecular dissection of t(11;17) in acute myeloid leukemia reveals a variety of gene fusions with heterogeneous fusion transcripts and multiple splice variants. Genes Chromosomes Cancer 45(11):1041–1049. doi:10.1002/gcc.20372

    Article  CAS  PubMed  Google Scholar 

  69. Licht JD, Chomienne C, Goy A, Chen A, Scott AA, Head DR, Michaux JL, Wu Y, DeBlasio A, Miller WH Jr et al (1995) Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85(4):1083–1094

    CAS  PubMed  Google Scholar 

  70. Mitani K, Kanda Y, Ogawa S, Tanaka T, Inazawa J, Yazaki Y, Hirai H (1995) Cloning of several species of MLL/MEN chimeric cDNAs in myeloid leukemia with t(11;19)(q23;p13.1) translocation. Blood 85(8):2017–2024

    CAS  PubMed  Google Scholar 

  71. Kakihana K, Kubo F, Wakabayashi S, Kurosu T, Miki T, Murakami N, Miura O (2008) A novel variant form of MLL-ELL fusion transcript with t(11;19)(q23;p13.1) in chronic myelomonocytic leukemia transforming to acute myeloid leukemia. Cancer Genet Cytogenet 184(2):109–112. doi:10.1016/j.cancergencyto.2008.04.001

    Article  CAS  PubMed  Google Scholar 

  72. Uphoff CC, MacLeod RA, Denkmann SA, Golub TR, Borkhardt A, Janssen JW, Drexler HG (1997) Occurrence of TEL-AML1 fusion resulting from (12;21) translocation in human early B-lineage leukemia cell lines. Leukemia 11(3):441–447

    Article  CAS  PubMed  Google Scholar 

  73. Romana SP, Mauchauffe M, Le Coniat M, Chumakov I, Le Paslier D, Berger R, Bernard OA (1995) The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion. Blood 85(12):3662–3670

    CAS  PubMed  Google Scholar 

  74. Abdelhaleem M, Yi Q, Beimnet K, Hitzler J (2006) A novel TEL-AML1 fusion transcript involving the pro-apoptotic gene BCL-G in pediatric precursor B acute lymphoblastic leukemia. Leukemia 20(7):1294. doi:10.1038/sj.leu.2404249

    Article  CAS  PubMed  Google Scholar 

  75. Park TS, Kim JS, Song J, Lee KA, Yoon S, Suh B, Lee JH, Lee HJ, Kim JK, Choi JR (2009) Acute promyelocytic leukemia with insertion of PML exon 7a and partial deletion of exon 3 of RARA: a novel variant transcript related to aggressive course and not detected with real-time polymerase chain reaction analysis. Cancer Genet Cytogenet 188(2):103–107. doi:10.1016/j.cancergencyto.2008.09.002

    Article  CAS  PubMed  Google Scholar 

  76. Lim G, Cho EH, Cho SY, Shin SY, Park JC, Yang YJ, Oh SH, Marschalek R, Meyer C, Park TS (2011) A novel PML-ADAMTS17-RARA gene rearrangement in a patient with pregnancy-related acute promyelocytic leukemia. Leuk Res 35(7):e106–e110. doi:10.1016/j.leukres.2011.03.020

    Article  CAS  PubMed  Google Scholar 

  77. Hiorns LR, Min T, Swansbury GJ, Zelent A, Dyer MJ, Catovsky D (1994) Interstitial insertion of retinoic acid receptor-alpha gene in acute promyelocytic leukemia with normal chromosomes 15 and 17. Blood 83(10):2946–2951

    CAS  PubMed  Google Scholar 

  78. Vizmanos JL, Larrrayoz MJ, Odero MD, Lasa R, Gonzalez M, Novo FJ, Calasanz MJ (2002) Two new molecular PML-RARalpha variants: implications for the molecular diagnosis of APL. Haematologica 87(8):ELT37

    PubMed  Google Scholar 

  79. Zayed A, Couban S, Hayne O, Sparavalo N, Shawwa A, Sadek I, Greer W (2007) Acute promyelocytic leukemia: a novel PML/RARalpha fusion that generates a frameshift in the RARalpha transcript and ATRA resistance. Leuk Lymphoma 48(3):489–496. doi:10.1080/10428190601136163

    Article  CAS  PubMed  Google Scholar 

  80. Oh SJ, Park TS, Lee JY, Mun YC, Seong CM, Marschalek R, Meyer C, Chung WS, Huh J (2013) Acute promyelocytic leukemia with a rare PML exon 4/ RARA exon 3 fusion transcript variant. Acta Haematol 130(3):176–180. doi:10.1159/000348551

    Article  PubMed  Google Scholar 

  81. Jeziskova I, Razga F, Gazdova J, Doubek M, Jurcek T, Koristek Z, Mayer J, Dvorakova D (2010) A case of a novel PML/RARA short fusion transcript with truncated transcription variant 2 of the RARA gene. Mol Diagn Ther 14(2):113–117. doi:10.2165/11317400-000000000-00000

    Article  CAS  PubMed  Google Scholar 

  82. Kong XT, Ida K, Ichikawa H, Shimizu K, Ohki M, Maseki N, Kaneko Y, Sako M, Kobayashi Y, Tojou A, Miura I, Kakuda H, Funabiki T, Horibe K, Hamaguchi H, Akiyama Y, Bessho F, Yanagisawa M, Hayashi Y (1997) Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16;21)(p11;q22) and identification of a novel transcript. Blood 90(3):1192–1199

    CAS  PubMed  Google Scholar 

  83. Cocce MC, Alonso CN, Rossi J, Felice MS, Gitter MR, Gallego MS (2015) A case of pediatric ALL with t(16;21)(p11.2;q22) and FUS-ERG rearrangement. Blood Res 50(1):55–58. doi:10.5045/br.2015.50.1.55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ichikawa H, Shimizu K, Hayashi Y, Ohki M (1994) An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation. Cancer Res 54(11):2865–2868

    CAS  PubMed  Google Scholar 

  85. Jiang H, Qiu H, Xue Y, Pan J, Wu Y, Zhang J, Zheng J, Wang Q, Liang J, Chen S (2011) Establishment and characterization of a novel acute myeloid leukemia cell line, JIH-4, carrying a t(16;21)(p11.2;q22) and expressing the FUS-ERG fusion. Cancer Genet 204(4):219–223. doi:10.1016/j.cancergen.2011.02.005

    Article  CAS  PubMed  Google Scholar 

  86. Takahashi H, Goto H, Eunabiki T, Fujii H, Yamazaki S, Fujioka K, Ikuta K, Kai S (2001) Expression of two types of E2A-HLF fusion proteins in YCUB-2, a novel cell line established from B-lineage leukemia with t(17;19). Leukemia 15(6):995–997

    Article  CAS  PubMed  Google Scholar 

  87. Hunger SP, Devaraj PE, Foroni L, Secker-Walker LM, Cleary ML (1994) Two types of genomic rearrangements create alternative E2A-HLF fusion proteins in t(17;19)-ALL. Blood 83(10):2970–2977

    CAS  PubMed  Google Scholar 

  88. Panagopoulos I, Micci F, Thorsen J, Haugom L, Tierens A, Ulvmoen A, Heim S (2012) A novel TCF3-HLF fusion transcript in acute lymphoblastic leukemia with a t(17;19)(q22;p13). Cancer Genet 205(12):669–672. doi:10.1016/j.cancergen.2012.10.004

    Article  CAS  PubMed  Google Scholar 

  89. Pui C-H (2006) Childhood leukemias, 2nd edn. Cambridge University Press, Cambridge

    Book  Google Scholar 

  90. Steinleitner K, Rampetsreiter P, Koffel R, Ramanathan G, Mannhalter C, Strobl H, Wieser R (2012) EVI1 and MDS1/EVI1 expression during primary human hematopoietic progenitor cell differentiation into various myeloid lineages. Anticancer Res 32(11):4883–4889

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Kustikova OS, Schwarzer A, Stahlhut M, Brugman MH, Neumann T, Yang M, Li Z, Schambach A, Heinz N, Gerdes S, Roeder I, Ha TC, Steinemann D, Schlegelberger B, Baum C (2013) Activation of Evi1 inhibits cell cycle progression and differentiation of hematopoietic progenitor cells. Leukemia 27(5):1127–1138. doi:10.1038/leu.2012.355

    Article  CAS  PubMed  Google Scholar 

  92. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel-van de Luytgaarde S, Hack R, Slater R, Smit EM, Beverloo HB, Verhoef G, Verdonck LF, Ossenkoppele GJ, Sonneveld P, de Greef GE, Lowenberg B, Delwel R (2003) High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood 101(3):837–845. doi:10.1182/blood-2002-05-1459

    Article  PubMed  Google Scholar 

  93. Su G, Lian X, Tan D, Tao H, Liu H, Chen S, Yin H, Wu D, Yin B (2015) Aberrant expression of ecotropic viral integration site-1 in acute myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma 56(2):472–479. doi:10.3109/10428194.2014.924118

    Article  CAS  PubMed  Google Scholar 

  94. Russell M, List A, Greenberg P, Woodward S, Glinsmann B, Parganas E, Ihle J, Taetle R (1994) Expression of EVI1 in myelodysplastic syndromes and other hematologic malignancies without 3q26 translocations. Blood 84(4):1243–1248

    CAS  PubMed  Google Scholar 

  95. Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, Behm FG, Pui CH, Downing JR, Gilliland DG, Lander ES, Golub TR, Look AT (2002) Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1(1):75–87

    Article  CAS  PubMed  Google Scholar 

  96. Hatano M, Roberts CW, Minden M, Crist WM, Korsmeyer SJ (1991) Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia. Science 253(5015):79–82

    Article  CAS  PubMed  Google Scholar 

  97. O'Neil J, Look AT (2007) Mechanisms of transcription factor deregulation in lymphoid cell transformation. Oncogene 26(47):6838–6849. doi:10.1038/sj.onc.1210766

    Article  PubMed  Google Scholar 

  98. Lichty BD, Ackland-Snow J, Noble L, Kamel-Reid S, Dube ID (1995) Dysregulation of HOX11 by chromosome translocations in T-cell acute lymphoblastic leukemia: a paradigm for homeobox gene involvement in human cancer. Leuk Lymphoma 16(3–4):209–215. doi:10.3109/10428199509049759

    Article  CAS  PubMed  Google Scholar 

  99. Brake RL, Kees UR, Watt PM (2002) A complex containing PBX2 contributes to activation of the proto-oncogene HOX11. Biochem Biophys Res Commun 294(1):23–34. doi:10.1016/S0006-291X(02)00426-6

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Special thanks to Dr. Reza Rahbarghazi (Tabriz University of Medical Science, Iran) for supplying the cell lines K562 and NALM-6. We appreciate the Hematology and Oncology and also Connective Tissue Disease Research Centers (Tabriz University of Medical Science, Tabriz, Iran) for financing the present study.

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Authors and Affiliations

  1. Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Faramarz Ghasemian Sorbeni & Ali Esfahani

  2. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Soheila Montazersaheb

  3. Tabriz Genetic Analysis Center (TGAC), Tabriz University of Medical Sciences, Tabriz, Iran

    Atefeh Ansarin

  4. Department of Pediatrics, Children Hospital, Tabriz University of Medical Sciences, Tabriz, Iran

    Azim Rezamand

  5. Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Ebrahim Sakhinia

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  1. Faramarz Ghasemian Sorbeni
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  2. Soheila Montazersaheb
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  3. Atefeh Ansarin
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  4. Ali Esfahani
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  5. Azim Rezamand
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  6. Ebrahim Sakhinia
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Contributions

FGS and ES, data collection and design of study; ES, standardization and management of research procedures; FGS, perform the molecular investigations on patient samples and cell lines; FGS, responsibility for the first draft of the manuscript; SM, implementation of process related to the preparation of cell lines; FGS and AA, RNA preparation; AE and AR, pathological assessment of patients and introduce them for sampling.

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Correspondence to Ebrahim Sakhinia.

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Ghasemian Sorbeni, F., Montazersaheb, S., Ansarin, A. et al. Molecular analysis of more than 140 gene fusion variants and aberrant activation of EVI1 and TLX1 in hematological malignancies. Ann Hematol 96, 1605–1623 (2017). https://doi.org/10.1007/s00277-017-3075-x

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  • DOI: https://doi.org/10.1007/s00277-017-3075-x

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