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Somatic mutations in acute promyelocytic leukemia (APL) identified by exome sequencing

Leukemia volume 25, pages 1519–1522 (2011)Cite this article

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The t(15;17) translocation that results in the PML/RARA fusion is the disease-defining lesion in nearly all cases of acute promyelocytic leukemia (APL).1 Despite the importance of the PML/RARA fusion for the pathogenesis of APL, it is most likely not sufficient to cause leukemia. The long latency, incomplete penetrance and additional cytogenetic changes accompanying the onset and progression of the disease in the murine APL models strongly suggest that additional mutations are required for the development of APL.2 In newly diagnosed patients with APL, approximately 40% have leukemic cells with secondary abnormalities.3 Collaborating mutations affecting the FLT3 receptor tyrosine kinase are found in about 20–30% of APL patients and a synergism between FLT3 mutations and PML/RARA was also observed in murine APL models.4

Recently, we used whole transcriptome sequencing to screen systematically for leukemia-specific mutations in a patient with karyotypically normal acute myeloid leukemia (AML).5 As an alternative approach, in the present study, we performed whole-exome sequencing of three APL patients to identify somatic mutations. All patients were diagnosed with PML/RARA-positive APL and achieved complete remission, following treatment with arsenic trioxide at the Shariati Hospital in Tehran (Iran).6 Mutations in FLT3 and NPM1 were excluded for all the three APL patients. After leukocyte recovery, a remission sample from peripheral blood was taken. Informed consent and ethical approval for scientific use of the sample including genetic studies was obtained. Genomic DNA was extracted from the patients’ bone marrow (diagnostic APL samples) or peripheral blood (remission samples).

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References

  1. de Thé H, 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: 558–561.

    Article  Google Scholar 

  2. Zimonjic DB, Pollock JL, Westervel P, Popescu NC, Ley TJ . Acquired, nonrandom chromosomal abnormalities associated with the development of acute promyelocytic leukemia in transgenic mice. Proc Natl Acad Sci 2000; 97: 13306–13311.

    Article  CAS  Google Scholar 

  3. Akagi T, Shih LY, Kato M, Kawamata N, Yamamoto G, Sanada M et al. Hidden abnormalities and novel classification of t(15;17) acute promyelocytic leukemia (APL) based on genomic alterations. Blood 2009; 113: 1741–1748.

    Article  CAS  Google Scholar 

  4. Kelly LM, Kutok JL, Williams IR, Boulton CL, Amaral SM, Curley DP et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci USA 2002; 99: 8283–8288.

    Article  CAS  Google Scholar 

  5. Greif PA, Eck SH, Konstandin NP, Benet-Pages A, Ksienzyk B, Dufour A et al. Identification of recurring tumor-specific somatic mutations in acute myeloid leukemia by transcriptome sequencing. Leukemia 2011; 25: 821–827.

    Article  CAS  Google Scholar 

  6. Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, Rostami S, Jahani M, Hosseini R et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol 2006; 17: 131–134.

    Article  CAS  Google Scholar 

  7. Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 2008; 456: 66–72.

    Article  CAS  Google Scholar 

  8. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361: 1058–1066.

    Article  CAS  Google Scholar 

  9. Paschka P, Marcucci G, Ruppert AS, Whitman SP, Mrozek K, Maharry K et al. Wilms′ tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 2008; 26: 4595–4602.

    Article  CAS  Google Scholar 

  10. Chan IT, Kutok JL, Williams IR, Cohen S, Moore S, Shigematsu H et al. Oncogenic K-ras cooperates with PML-RAR alpha to induce an acute promyelocytic leukemia-like disease. Blood 2006; 108: 1708–1715.

    Article  CAS  Google Scholar 

  11. Eklund EA . The role of HOX genes in malignant myeloid disease. Curr Opin Hematol 2007; 14: 85–89.

    Article  CAS  Google Scholar 

  12. Okamoto M, Hayakawa F, Miyata Y, Watamoto K, Emi N, Abe A et al. Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD. Leukemia 2007; 21: 403–410.

    Article  CAS  Google Scholar 

  13. Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T et al. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood 2008; 111: 4797–4808.

    Article  CAS  Google Scholar 

  14. Chun EM, Park YJ, Kang HS, Cho HM, Jun DY, Kim YH . Expression of the apolipoprotein C-II gene during myelomonocytic differentiation of human leukemic cells. J Leukoc Biol 2001; 69: 645–650.

    CAS  PubMed  Google Scholar 

  15. Weinberg JB, Volkheimer AD, Mihovilovic M, Jiang N, Chen Y, Bond K et al. Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia. Leukemia 2008; 22: 2184–2192.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was funded by a Deutsche Krebshilfe grant (109031) to PAG and SKB, and a grant from the BMBF to SKB (NGFN Plus, PKL-01-GS0876-6).

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Authors and Affiliations

  1. Clinical Cooperative Group ‘Leukemia’, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany

    P A Greif, M Yaghmaie, N P Konstandin, B Ksienzyk & S K Bohlander

  2. Department of Medicine III, Universität München, Munich, Germany

    P A Greif, M Yaghmaie, N P Konstandin, B Ksienzyk & S K Bohlander

  3. Haematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

    M Yaghmaie, K Alimoghaddam & A Ghavamzadeh

  4. Laboratory for Functional Genome Analysis (LaFuGA), Gene-Center, Universität München, Munich, Germany

    A Graf, S Krebs & H Blum

  5. Computational Biology, Gene-Center, Universität München, Munich, Germany

    A Hauser

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  1. P A Greif
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  2. M Yaghmaie
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Correspondence to P A Greif or S K Bohlander.

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Greif, P., Yaghmaie, M., Konstandin, N. et al. Somatic mutations in acute promyelocytic leukemia (APL) identified by exome sequencing. Leukemia 25, 1519–1522 (2011). https://doi.org/10.1038/leu.2011.114

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