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.

  • Letter to the Editor
  • Published:

All-trans retinoic acid and arsenic trioxide resistance of acute promyelocytic leukemia with the variant STAT5B-RARA fusion gene

Leukemia volume 27, pages 1606–1610 (2013)Cite this article

Subjects

The genetic hallmark of acute promyelocytic leukemia (APL) is the t(15;17)(q22;q21)/PML-RARA rearrangement, which is detectable by fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR) in >95% of morphologically defined APL.1, 2 Moreover, seven variant fusion genes, which fuse RARA at low frequency to ZBTB16 or very rarely to NPM1, NUMA1, PRKAR1A, FIP1L1, BCOR and STAT5B have been described.2, 3, 4, 5

Prolonged disease-free survival of APL patients is achieved by combining all-trans retinoic acid (ATRA) and chemotherapy.6 In addition, treatment with arsenic trioxide (ATO) is of proven value in relapsed disease and also effective during induction or consolidation therapy or both.5, 6, 7 However, the RARA fusion partner has an important impact on the biology of the disease, in particular with regard to retinoic acid (RA) sensitivity. Therefore, APL can be divided in two disease subtypes: a RA-responsive subtype, which includes APL with RARA fusions to PML, NPM1 and NuMA, and possibly also to BCOR, PRKAR1A and FIP1L1; and a RA-unresponsiveness subtype characterized by the presence of the ZBTB16-RARA and most probably the STAT5B-RARA fusions.1, 2, 3, 4 The sensitivity of variant RARA fusions to ATO has not been well documented, but ZBTB16–RARA-positive APL appears to be resistant.2, 5 In this respect, it is noteworthy that the direct interaction of ATO with the PML moiety of the PML-RARA fusion protein leading to its degradation may provide an explanation for the specificity of ATO treatment in PML-RARA-positive APL.8

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

References

  1. Grimwade D, Biondi A, Mozziconacci MJ, Hagemeijer A, Berger R, Neat M et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Francais de Cytogenetique Hematologique, Groupe de Francais d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action ‘Molecular Cytogenetic Diagnosis in Haematological Malignancies'. Blood 2000; 96: 1297–1308.

    CAS  PubMed  Google Scholar 

  2. Mistry AR, Pedersen EW, Solomon E, Grimwade D . The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease. Blood Rev 2003; 17: 71–97.

    Article  PubMed  Google Scholar 

  3. Catalano A, Dawson MA, Somana K, Opat S, Schwarer A, Campbell LJ et al. The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia. Blood 2007; 110: 4073–4076.

    Article  CAS  PubMed  Google Scholar 

  4. Yamamoto Y, Tsuzuki S, Tsuzuki M, Handa K, Inaguma Y, Emi N . BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia. Blood 2010; 116: 4274–4283.

    Article  CAS  PubMed  Google Scholar 

  5. Lengfelder E, Hofmann WK, Nowak D . Impact of arsenic trioxide in the treatment of acute promyelocytic leukemia. Leukemia 2012; 26: 433–442.

    Article  CAS  PubMed  Google Scholar 

  6. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009; 113: 1875–1891.

    Article  CAS  PubMed  Google Scholar 

  7. Creutzig U, Zimmermann M, Dworzak M, Urban C, Henze G, Kremens B et al. Favourable outcome of patients with childhood acute promyelocytic leukaemia after treatment with reduced cumulative anthracycline doses. Br J Haematol 2010; 149: 399–409.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB et al. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 2010; 328: 240–243.

    Article  CAS  PubMed  Google Scholar 

  9. Arnould C, Philippe C, Bourdon V, Gregoire MJ, Berger R, Jonveaux P . The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia. Hum Mol Genet 1999; 8: 1741–1749.

    Article  CAS  PubMed  Google Scholar 

  10. Gallagher RE, Mak S, Paietta E, Cooper B, Ehmann WC, Tallman MS . Identification of a second acute promyelocytic leukemia (APL) patient with the STAT5b-RAR fusion gene among PML-RAR -negative Eastern Cooperative Oncology Group (ECOG) APL Protocol Registrants. Blood 2004; 104: 821a.

    Google Scholar 

  11. Kusakabe M, Suzukawa K, Nanmoku T, Obara N, Okoshi Y, Mukai HY et al. Detection of the STAT5B-RARA fusion transcript in acute promyelocytic leukemia with the normal chromosome 17 on G-banding. Eur J Haematol 2008; 80: 444–447.

    Article  CAS  PubMed  Google Scholar 

  12. Iwanaga E, Nakamura M, Nanri T, Kawakita T, Horikawa K, Mitsuya H et al. Acute promyelocytic leukemia harboring a STAT5B-RARA fusion gene and a G596V missense mutation in the STAT5B SH2 domain of the STAT5B-RARA. Eur J Haematol 2009; 83: 499–501.

    Article  CAS  PubMed  Google Scholar 

  13. Qiao C, Zhang SJ, Chen LJ, Miao KR, Zhang JF, Wu YJ et al. Identification of the STAT5B-RARalpha fusion transcript in an acute promyelocytic leukemia patient without FLT3, NPM1, c-Kit and C/EBPalpha mutation. Eur J Haematol 2011; 86: 442–446.

    Article  CAS  PubMed  Google Scholar 

  14. Jovanovic JV, Rennie K, Culligan D, Peniket A, Lennard A, Harrison J et al. Development of real-time quantitative polymerase chain reaction assays to track treatment response in retinoid resistant acute promyelocytic leukemia. Front Oncol 2011; 1: 35.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chen H, Pan J, Yao L, Wu L, Zhu J, Wang W et al. Acute promyelocytic leukemia with a STAT5b-RARalpha fusion transcript defined by array-CGH, FISH, and RT-PCR. Cancer Genet 2012; 205: 327–331.

    Article  CAS  PubMed  Google Scholar 

  16. Schnittger S, Bacher U, Haferlach C, Kern W, Alpermann T, Haferlach T . Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA. Haematologica 2011; 96: 1799–1807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the St. Anna Kinderkrebsforschung e.V. The authors would like to thank Robert E Gallagher for critically reviewing the manuscript and Angela Schumich for conducting the FACS analysis.

Author Contributions

SS initiated the study, collected all clinical data and drafted the manuscript. MK conducted FISH and molecular experiments. MND is responsible for the flow cytometric data. HB, BWC, AA and MND contributed to the writing of the manuscript. HB, BWC, KS, S-JZ, H-YC, AA and MND provided, and are responsible for the clinical data. All authors gave their final approval of the manuscript.

Author information

Authors and Affiliations

  1. CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung e.V, Vienna, Austria

    S Strehl, M König & M N Dworzak

  2. Department of Pediatrics, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria

    H Boztug, A Attarbaschi & M N Dworzak

  3. University Hospitals of Cleveland, Case Medical Center, Cleveland, OH, USA

    B W Cooper

  4. Department of Hematology, Division of Clinical Medicine, University of Tsukuba, Ibaraki, Japan

    K Suzukawa

  5. First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    S-J Zhang

  6. Jingjiang People's Hospital, Jiangsu Province, China

    H-Y Chen

Authors
  1. S Strehl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M König
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Boztug
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B W Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Suzukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S-J Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H-Y Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Attarbaschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M N Dworzak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Strehl.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Strehl, S., König, M., Boztug, H. et al. All-trans retinoic acid and arsenic trioxide resistance of acute promyelocytic leukemia with the variant STAT5B-RARA fusion gene. Leukemia 27, 1606–1610 (2013). https://doi.org/10.1038/leu.2012.371

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.371

Search

Advanced search

Quick links