Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Myelodysplasias

Acute myeloid leukemia bearing t(7;11)(p15;p15) is a distinct cytogenetic entity with poor outcome and a distinct mutation profile: comparative analysis of 493 adult patients

Abstract

Acute myeloid leukemia (AML) with t(7;11)(p15;p15), which results in a NUP98HOXA9 fusion, is a distinct entity, but this subtype has not been characterized in detail. In a comprehensive study comparing 11 such patients with another 482 adult patients, we found that those with t(7;11) were younger (P=0.0076) and female (P=0.0111), with almost all having the M2-subtype of AML (P<0.0001). Even when those with low-risk karyotypes were excluded, patients with t(7;11) had poorer overall survival than the other AML group (median 13.5 and 20 months, respectively, P=0.045) and poorer relapse-free survival (median 6 and 12 months, respectively, P=0.003). The NUP98–HOXA9 fusion was strongly associated with KRAS and WT1 mutations (P=0.015 and P=0.0018, respectively). We characterized four varieties of this fusion, among which NUP98 exon 12/HOXA9 exon 1b was present in all 11 patients. We developed a highly sensitive and specific assay to quantify the abundance of leukemic cells, and found that the fusion remained detectable in morphological complete remission, even after allogeneic stem cell transplantation, suggesting that this disease was highly refractory to very intensive treatment. AML with NUP98HOXA9 fusion therefore appears to have a distinct clinical and biological profile, and should be regarded as a poor prognostic group.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. Ohyashiki K . Nonrandom cytogenetic changes in human acute leukemia and their clinical implications. Cancer Genet Cytogenet 1984; 11: 453–471.

    Article  CAS  PubMed  Google Scholar 

  2. Okada M, Mizoguchi H, Kubota K, Nomura Y . Quantitative analysis of chromosomal G-bands in human hematopoietic disorders by methotrexate synchronization technique. Cancer Genet Cytogenet 1984; 13: 225–237.

    Article  CAS  PubMed  Google Scholar 

  3. Sato Y, Abe S, Mise K, Sasaki M, Kamada N, Kouda K et al. Reciprocal translocation involving the short arms of chromosomes 7 and 11, t(7p−;11p+), associated with myeloid leukemia with maturation. Blood 1987; 70: 1654–1658.

    CAS  PubMed  Google Scholar 

  4. Huang SY, Tang JL, Liang YJ, Wang CH, Chen YC, Tien HF . Clinical, haematological and molecular studies in patients with chromosome translocation t(7;11): a study of four Chinese patients in Taiwan. Br J Haematol 1997; 96: 682–687.

    Article  CAS  PubMed  Google Scholar 

  5. Kwong YL, Liu HW, Chan LC . Racial predisposition to translocation (7;11). Leukemia 1992; 6: 232.

    CAS  PubMed  Google Scholar 

  6. Kwong YL, Chan TK . Translocation (7;11)(p15;p15) in acute myeloid leukemia M2: association with trilineage myelodysplasia and giant dysplastic myeloid cells. Am J Hematol 1994; 47: 62–64.

    Article  CAS  PubMed  Google Scholar 

  7. Kwong YL, Pang A . Low frequency of rearrangements of the homeobox gene HOXA9/t(7;11) in adult acute myeloid leukemia. Genes Chromosomes Cancer 1999; 25: 70–74.

    Article  CAS  PubMed  Google Scholar 

  8. Inaba T, Shimazaki C, Yoneyama S, Hirai H, Kikuta T, Sumikuma T et al. t(7;11) and trilineage myelodysplasia in acute myelomonocytic leukemia. Cancer Genet Cytogenet 1996; 86: 72–75.

    Article  CAS  PubMed  Google Scholar 

  9. Hatano Y, Miura I, Nakamura T, Yamazaki Y, Takahashi N, Miura AB . Molecular heterogeneity of the NUP98/HOXA9 fusion transcript in myelodysplastic syndromes associated with t(7;11)(p15;p15). Br J Haematol 1999; 107: 600–604.

    Article  CAS  PubMed  Google Scholar 

  10. Ahuja HG, Popplewell L, Tcheurekdjian L, Slovak ML . NUP98 gene rearrangements and the clonal evolution of chronic myelogenous leukemia. Genes Chromosomes Cancer 2001; 30: 410–415.

    Article  CAS  PubMed  Google Scholar 

  11. Yamamoto K, Nakamura Y, Saito K, Furusawa S . Expression of the NUP98/HOXA9 fusion transcript in the blast crisis of Philadelphia chromosome-positive chronic myelogenous leukaemia with t(7;11)(p15;p15). Br J Haematol 2000; 109: 423–426.

    Article  CAS  PubMed  Google Scholar 

  12. Wong KF, So CC, Kwong YL . Chronic myelomonocytic leukemia with t(7;11)(p15;p15) and NUP98/HOXA9 fusion. Cancer Genet Cytogenet 1999; 115: 70–72.

    Article  CAS  PubMed  Google Scholar 

  13. Suzuki A, Ito Y, Sashida G, Honda S, Katagiri T, Fujino T et al. t(7;11)(p15;p15) Chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion. Br J Haematol 2002; 116: 170–172.

    Article  CAS  PubMed  Google Scholar 

  14. Kaneko Y, Maseki N, Takasaki N, Sakurai M, Kawai K, Sakurai M . Possible association of a new translocation, t(7;11)(p15;p15), with Ph1 chromosome-negative chronic myelogenous leukemia. Int J Cancer 1985; 36: 657–659.

    Article  CAS  PubMed  Google Scholar 

  15. Takeda T, Ikebuchi K, Zaike Y, Mori M, Ohyashiki K, Ikeuchi T . Ph-negative chronic myelocytic leukemia with a complex translocation involving chromosomes 7 and 11. Cancer Genet Cytogenet 1986; 21: 123–127.

    Article  CAS  PubMed  Google Scholar 

  16. Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet 1996; 12: 154–158.

    Article  CAS  PubMed  Google Scholar 

  17. Borrow J, Shearman AM, Stanton Jr VP, Becher R, Collins T, Williams AJ et al. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nat Genet 1996; 12: 159–167.

    Article  CAS  PubMed  Google Scholar 

  18. Nakamura T, Yamazaki Y, Hatano Y, Miura I . NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15). Blood 1999; 94: 741–747.

    CAS  PubMed  Google Scholar 

  19. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, Aplan PD . NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia. Cancer Res 1998; 58: 4269–4273.

    CAS  PubMed  Google Scholar 

  20. Taketani T, Taki T, Ono R, Kobayashi Y, Ida K, Hayashi Y . The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9. Genes Chromosomes Cancer 2002; 34: 437–443.

    Article  CAS  PubMed  Google Scholar 

  21. Panagopoulos I, Isaksson M, Billstrom R, Strombeck B, Mitelman F, Johansson B . Fusion of the NUP98 gene and the homeobox gene HOXC13 in acute myeloid leukemia with t(11;12)(p15;q13). Genes Chromosomes Cancer 2003; 36: 107–112.

    Article  CAS  PubMed  Google Scholar 

  22. Nishiyama M, Arai Y, Tsunematsu Y, Kobayashi H, Asami K, Yabe M et al. 11p15 translocations involving the NUP98 gene in childhood therapy-related acute myeloid leukemia/myelodysplastic syndrome. Genes Chromosomes Cancer 1999; 26: 215–220.

    Article  CAS  PubMed  Google Scholar 

  23. Kroon E, Thorsteinsdottir U, Mayotte N, Nakamura T, Sauvageau G . NUP98-HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice. EMBO J 2001; 20: 350–361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mayotte N, Roy DC, Yao J, Kroon E, Sauvageau G . Oncogenic interaction between BCR-ABL and NUP98-HOXA9 demonstrated by the use of an in vitro purging culture system. Blood 2002; 100: 4177–4184.

    Article  CAS  PubMed  Google Scholar 

  25. Dash AB, Williams IR, Kutok JL, Tomasson MH, Anastasiadou E, Lindahl K et al. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc Natl Acad Sci USA 2002; 99: 7622–7627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chung KY, Morrone G, Schuringa JJ, Plasilova M, Shieh JH, Zhang Y et al. Enforced expression of NUP98-HOXA9 in human CD34(+) cells enhances stem cell proliferation. Cancer Res 2006; 66: 11781–11791.

    Article  CAS  PubMed  Google Scholar 

  27. Takeda A, Goolsby C, Yaseen NR . NUP98-HOXA9 induces long-term proliferation and blocks differentiation of primary human CD34+ hematopoietic cells. Cancer Res 2006; 66: 6628–6637.

    Article  CAS  PubMed  Google Scholar 

  28. Tien HF, Wang CH, Lin MT, Lee FY, Liu MC, Chuang SM et al. Correlation of cytogenetic results with immunophenotype, genotype, clinical features, and ras mutation in acute myeloid leukemia. A study of 235 Chinese patients in Taiwan. Cancer Genet Cytogenet 1995; 84: 60–68.

    Article  CAS  PubMed  Google Scholar 

  29. Lin LI, Chen CY, Lin DT, Tsay W, Tang JL, Yeh YC et al. Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clin Cancer Res 2005; 11: 1372–1379.

    Article  CAS  PubMed  Google Scholar 

  30. Chou WC, Tang JL, Lin LI, Yao M, Tsay W, Chen CY et al. Nucleophosmin mutations in de novo acute myeloid leukemia: the age-dependent incidences and the stability during disease evolution. Cancer Res 2006; 66: 3310–3316.

    Article  CAS  PubMed  Google Scholar 

  31. Chen CY, Lin LI, Tang JL, Ko BS, Tsay W, Chou WC et al. RUNX1 gene mutation in primary myelodysplastic syndrome—the mutation can be detected early at diagnosis or acquired during disease progression and is associated with poor outcome. Br J Haematol 2007; 139: 405–414.

    Article  CAS  PubMed  Google Scholar 

  32. Hou HA, Chou WC, Lin LI, Chen CY, Tang JL, Tseng MH et al. Characterization of acute myeloid leukemia with PTPN11 mutation: the mutation is closely associated with NPM1 mutation but inversely related to FLT3/ITD. Leukemia 2008; 22: 1075–1078.

    Article  CAS  PubMed  Google Scholar 

  33. Summers K, Stevens J, Kakkas I, Smith M, Smith LL, Macdougall F et al. Wilms’ tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia 2007; 21: 550–551.

    Article  CAS  PubMed  Google Scholar 

  34. Chou WC, Tang JL, Wu SJ, Tsay W, Yao M, Huang SY et al. Clinical implications of minimal residual disease monitoring by quantitative polymerase chain reaction in acute myeloid leukemia patients bearing nucleophosmin (NPM1) mutations. Leukemia 2007; 21: 998–1004.

    Article  CAS  PubMed  Google Scholar 

  35. Kelly LM, Gilliland DG . Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet 2002; 3: 179–198.

    Article  CAS  PubMed  Google Scholar 

  36. Frohling S, Scholl C, Gilliland DG, Levine RL . Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol 2005; 23: 6285–6295.

    Article  CAS  PubMed  Google Scholar 

  37. Romana SP, Radford-Weiss I, Ben Abdelali R, Schluth C, Petit A, Dastugue N et al. NUP98 rearrangements in hematopoietic malignancies: a study of the Groupe Francophone de Cytogenetique Hematologique. Leukemia 2006; 20: 696–706.

    Article  CAS  PubMed  Google Scholar 

  38. Iwasaki M, Kuwata T, Yamazaki Y, Jenkins NA, Copeland NG, Osato M et al. Identification of cooperative genes for NUP98-HOXA9 in myeloid leukemogenesis using a mouse model. Blood 2005; 105: 784–793.

    Article  CAS  PubMed  Google Scholar 

  39. Ellisen LW, Carlesso N, Cheng T, Scadden DT, Haber DA . The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells. EMBO J 2001; 20: 1897–1909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. King-Underwood L, Pritchard-Jones K . Wilms’ tumor (WT1) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance. Blood 1998; 91: 2961–2968.

    CAS  PubMed  Google Scholar 

  41. Bowen DT, Frew ME, Hills R, Gale RE, Wheatley K, Groves MJ et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood 2005; 106: 2113–2119.

    Article  CAS  PubMed  Google Scholar 

  42. Hanson RD, Hess JL, Yu BD, Ernst P, van Lohuizen M, Berns A et al. Mammalian Trithorax and polycomb-group homologues are antagonistic regulators of homeotic development. Proc Natl Acad Sci USA 1999; 96: 14372–14377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dellino GI, Schwartz YB, Farkas G, McCabe D, Elgin SC, Pirrotta V . Polycomb silencing blocks transcription initiation. Mol Cell 2004; 13: 887–893.

    Article  CAS  PubMed  Google Scholar 

  44. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C et al. The polycomb group protein EZH2 directly controls DNA methylation. Nature 2006; 439: 871–874.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants NSC 96-2628-B002-013-MY2 from National Science Council (Taiwan), NHRI-EX97-9731BI from National Health Research Institute (Taiwan) and YongLin Healthcare Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H-F Tien.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chou, WC., Chen, CY., Hou, HA. et al. Acute myeloid leukemia bearing t(7;11)(p15;p15) is a distinct cytogenetic entity with poor outcome and a distinct mutation profile: comparative analysis of 493 adult patients. Leukemia 23, 1303–1310 (2009). https://doi.org/10.1038/leu.2009.25

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2009.25

Keywords

This article is cited by

Search

Quick links