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.

  • Article
  • Published:

The mutational spectrum of FLT3 gene in acute lymphoblastic leukemia is different from acute myeloid leukemia

Cancer Gene Therapy volume 27, pages 81–88 (2020)Cite this article

Subjects

Abstract

Mutations in FMS-like tyrosine kinase 3 (FLT3) gene occur frequently in acute myeloid leukemia (AML) and are rare in acute lymphoblastic leukemia (ALL). We aimed to analyze the incidence and characteristics of FLT3 mutations in ALL. Amplicon-targeted next-generation sequencing of 58 genes was performed on 1571 patients (AML, n = 829; ALL, n = 742). FLT3 mutations were identified in 5.12% (38/742) of ALL patients. Four types of FLT3 mutations were disclosed, including internal tandem duplication (ITD), tyrosine kinase domain (TKD), juxtamembrane insertion and deletion (JM-INDEL), and juxtamembrane point mutation (JM-PM), which were respectively identified in 1.21, 1.89, 0.67, and 1.89% of patients. The incidence of FLT3-JM-PM (1.89 vs 0.48%, P = 0.009) and the proportion of TKD non-D835 mutations that accounted for the total TKD mutations (57.14 vs 18.18%, P = 0.013) were significantly higher in ALL when compared with AML. FLT3-JM-INDEL were mainly found in B-ALL. In addition, FLT3-JM-INDEL and FLT3-JM-PM were first reported in patients with B-ALL. Patients with FLT3 mutations besides of ITD and/or TKD had a potential response to tyrosine kinase inhibitors. We showed that the mutation spectrum of FLT3 gene in ALL is distinct from AML that will facilitated an in-depth understand of the pathogenesis and provide a guidance for treatment.

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

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. DiNardo CD, Cortes JE. Mutations in AML: prognostic and therapeutic implications. Hematol Am Soc Hematol Educ Program. 2016;2016:348–55.

    Article  Google Scholar 

  2. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.

    Article  CAS  Google Scholar 

  3. Zhang Y, Wang F, Chen X, Zhang Y, Wang M, Liu H, et al. CSF3R Mutations are frequently associated with abnormalities of RUNX1, CBFB, CEBPA, and NPM1 genes in acute myeloid leukemia. Cancer. 2018;124:3329–38.

    Article  CAS  Google Scholar 

  4. Chen X, Wang F, Zhang Y, Wang M, Tian W, Teng W, et al. Retrospective analysis of 36 fusion genes in 2479 Chinese patients of de novo acute lymphoblastic leukemia. Leuk Res. 2018;72:99–104.

    Article  CAS  Google Scholar 

  5. Li M, Datto M, Duncavage E, Kulkarni S, Lindeman N, Roy S, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for molecular pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19:4–23.

    Article  CAS  Google Scholar 

  6. Elyamany G, Awad M, Alsuhaibani O, Fadalla K, Al Sharif O, Al Shahrani M, et al. FLT3 internal tandem duplication and D835 mutations in patients with acute lymphoblastic leukemia and its clinical significance. Mediterr J Hematol Infect Dis. 2014;6:e2014038.

    Article  Google Scholar 

  7. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97:2434–9.

    Article  CAS  Google Scholar 

  8. Whitman SP, Ruppert AS, Radmacher MD, Mrózek K, Paschka P, Langer C, et al. FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications. Blood. 2008;111:1552–9.

    Article  CAS  Google Scholar 

  9. Alkhayat N, Elborai Y, Al Sharif O, Al Shahrani M, Alsuhaibani O, Awad M, et al. Cytogenetic profile and gene mutations of childhood acute lymphoblastic leukemia. Clin Med Insights Oncol. 2017;11:1179554917721710.

    Article  Google Scholar 

  10. Matsuno N, Nanri T, Kawakita T, Mitsuya H, Asou N. A novel FLT3 activation loop mutation N841K in acute myeloblastic leukemia. Leukemia. 2005;19:480–1.

    Article  CAS  Google Scholar 

  11. Li C, Liu L, Liang L, Xia Z, Li Z, Wang X, et al. AMG 925 is a dual FLT3/CDK4 inhibitor with the potential to overcome FLT3 inhibitor resistance in acute myeloid leukemia. Mol Cancer Ther. 2015;14:375–83.

    Article  CAS  Google Scholar 

  12. Kindler T, Breitenbuecher F, Kasper S, Estey E, Giles F, Feldman E, et al. Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML). Blood. 2005;105:335–40.

    Article  CAS  Google Scholar 

  13. Jiang J, Paez J, Lee J, Bo R, Stone R, DeAngelo D, et al. Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML. Blood. 2004;104:1855–8.

    Article  CAS  Google Scholar 

  14. Smith C, Zhang C, Lin K, Lasater E, Zhang Y, Massi E, et al. Characterizing and overriding the structural mechanism of the quizartinib-resistant FLT3 “Gatekeeper” F691L mutation with PLX3397. Cancer Discov. 2015;5:668–79.

    Article  CAS  Google Scholar 

  15. Smith C, Lasater E, Zhu X, Lin K, Stewart W, Damon L, et al. Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD. Blood. 2013;121:3165–71.

    Article  CAS  Google Scholar 

  16. Janke H, Pastore F, Schumacher D, Herold T, Hopfner KP, Schneider S, et al. Activating FLT3 mutants show distinct gain-of-function phenotypes in vitro and a characteristic signaling pathway profile associated with prognosis in acute myeloid leukemia. PLoS ONE. 2014;9:e89560.

    Article  Google Scholar 

  17. Grundler R, Thiede C, Miething C, Steudel C, Peschel C, Duyster J. Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. Blood. 2003;102:646–51.

    Article  CAS  Google Scholar 

  18. Kesarwani M, Huber E, Azam M. Overcoming AC220 resistance of FLT3-ITD by SAR302503. Blood Cancer J. 2013;3:e138.

    Article  CAS  Google Scholar 

  19. Cools J, Mentens N, Furet P, Fabbro D, Clark J, Griffin J, et al. Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res. 2004;64:6385–9.

    Article  CAS  Google Scholar 

  20. Man C, Fung T, Ho C, Han H, Chow H, Ma A, et al. Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood. 2012;119:5133–43.

    Article  CAS  Google Scholar 

  21. Chatain N, Perera R, Rossetti G, Rossa J, Carloni P, Schemionek M, et al. Rare FLT3 deletion mutants may provide additional treatment options to patients with AML: an approach to individualized medicine. Leukemia. 2015;29:2434–8.

    Article  CAS  Google Scholar 

  22. Sandhöfer N, Bauer J, Reiter K, Dufour A, Rothenberg M, Konstandin NP, et al. The new and recurrent FLT3 juxtamembrane deletion mutation shows a dominant negative effect on the wild-type FLT3 receptor. Sci Rep. 2016;6:28032.

    Article  Google Scholar 

  23. Meshinchi S, Stirewalt D, Alonzo T, Boggon T, Gerbing R, Rocnik J, et al. Structural and numerical variation of FLT3/ITD in pediatric AML. Blood. 2008;111:4930–3.

    Article  CAS  Google Scholar 

  24. Reindl C, Bagrintseva K, Vempati S, Schnittger S, Ellwart J, Wenig K, et al. Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML. Blood. 2006;107:3700–7.

    Article  CAS  Google Scholar 

  25. Fröhling S, Scholl C, Levine R, Loriaux M, Boggon T, Bernard O, et al. Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles. Cancer Cell. 2007;12:501–13.

    Article  Google Scholar 

  26. Syampurnawati M, Tatsumi E, Furuta K, Hayashi Y. Four novel point mutations in exons 12, 13, and 14 of the FLT3 gene. Leuk Res. 2007;31:877.

    Article  Google Scholar 

  27. Stirewalt D, Meshinchi S, Kussick S, Sheets K, Pogosova-Agadjanyan E, Willman C, et al. Novel FLT3 point mutations within exon 14 found in patients with acute myeloid leukaemia. Br J Haematol. 2004;124:481–4.

    Article  CAS  Google Scholar 

  28. Heiss E, Masson K, Sundberg C, Pedersen M, Sun J, Bengtsson S, et al. Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2. Blood. 2006;108:1542–50.

    Article  CAS  Google Scholar 

  29. Rocnik J, Okabe R, Yu J, Lee B, Giese N, Schenkein D, et al. Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood. 2006;108:1339–45.

    Article  CAS  Google Scholar 

  30. Tarlock K, Hansen ME, Hylkema T, Ries R, Farrar JE, Auvil JG, et al. Discovery and functional validation of novel pediatric specific FLT3 activating mutations in acute myeloid leukemia: results from the COG/NCI target initiative. Blood. 2015;126:87–87.

    Article  Google Scholar 

  31. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  Google Scholar 

  32. O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, et al. Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2017;15:926–57.

    Article  Google Scholar 

  33. Levis M. Midostaurin approved for FLT3-mutated AML. Blood. 2017;129:3403–6.

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally: Yu Zhang, Yang Zhang, Fang Wang

Authors and Affiliations

  1. Division of Pathology and Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Beijing, China

    Yu Zhang, Yang Zhang, Fang Wang, Mingyu Wang, Hong Liu, Xue Chen, Panxiang Cao, Xiaoli Ma, Wen Teng & Hongxing Liu

  2. Department of Hematology, Hebei Yanda Lu Daopei Hospital, Beijing, China

    Xian Zhang

  3. Beijing Lu Daopei Institute of Hematology, Beijing, China

    Hongxing Liu

Authors
  1. Yu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mingyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xue Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Panxiang Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaoli Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wen Teng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hongxing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongxing Liu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Zhang, Y., Wang, F. et al. The mutational spectrum of FLT3 gene in acute lymphoblastic leukemia is different from acute myeloid leukemia. Cancer Gene Ther 27, 81–88 (2020). https://doi.org/10.1038/s41417-019-0120-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-019-0120-z

This article is cited by

Search

Advanced search

Quick links