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Acute lymphoblastic leukemia

Leukemic cells expressing NCOR1-LYN are sensitive to dasatinib in vivo in a patient-derived xenograft mouse model

Leukemia volume 35, pages 2092–2096 (2021)Cite this article

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LYN kinase, one of the Src family kinases, is considered to be an ABL-class kinase [1]. Previously, we identified NCOR1-LYN as a novel fusion gene in pediatric acute lymphoblastic leukemia (ALL) patients with deletion of IKZF1 and a Philadelphia chromosome-like (Ph-like) gene expression signature [2]. Another study identified GATAD2A-LYN in a patient with Ph-like ALL [3]. Furthermore, the ETV6(TEL)-LYN fusion gene was identified in three patients with primary myelofibrosis, myeloproliferative neoplasm, and acute myeloid leukemia [4, 5]. Consistent with LYN kinase being a Src family kinase and ABL-class kinase, the tyrosine kinase inhibitor (TKI) dasatinib is effective against cells bearing the ETV6-LYN fusion gene [4]. Recently, a new case of relapsed ALL with NCOR1-LYN fusion was reported [5]. This patient achieved complete remission within 2 weeks after the dasatinib monotherapy, and then received haploidentical allogenic transplantation and maintenance therapy with dasatinib. The patient has been in MRD-negative remission for 10 months after transplantation. Collectively, these findings indicate that rearrangement of LYN is a recurrent genetic abnormality in Ph-like ALL and is a rational target for treatment with dasatinib. In this study, we performed functional analysis of the NCOR1-LYN fusion protein in vitro and, using a patient-derived xenograft (PDX) mouse model, evaluated the efficacy in vivo of targeting the LYN kinase domain with dasatinib.

Next, a Ba/F3-NCOR1-LYN mutant in which both tyrosine residues of LYN were replaced with phenylalanine (Y397F and Y508F) was established. Loss of tyrosine phosphorylation in the Ba/F3-NCOR1-LYN (Y397F and Y508F) mutant was confirmed by western blot analysis (Fig. 1C). The Ba/F3-NCOR1-LYN (Y397F and Y508F) mutant could not proliferate without IL-3 (Fig. 1D). Therefore, these data indicate that tyrosine phosphorylation of the LYN kinase domain is essential for proliferative activity.

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Fig. 1: Cell proliferation and gene expression of Ba/F3 cells induced by NCOR1-LYN.
Fig. 2: Effects of dasatinib and rapamycin on NCOR1-LYN.

References

  1. Roberts KG. Why and how to treat Ph-like ALL? Best Pr Res Clin Haematol. 2018;31(4):351–6.

    Article  Google Scholar 

  2. Yano M, Imamura T, Asai D, Kiyokawa N, Nakabayashi K, Matsumoto K, et al. Identification of novel kinase fusion transcripts in paediatric B cell precursor acute lymphoblastic leukaemia with IKZF1 deletion. Br J Haematol. 2015;171(5):813–7.

    Article  CAS  Google Scholar 

  3. Reshmi SC, Harvey RC, Roberts KG, Stonerock E, Smith A, Jenkins H, et al. Targetable kinase gene fusions in high-risk B-ALL: a study from the Children’s Oncology Group. Blood. 2017;129(25):3352–61.

    Article  CAS  Google Scholar 

  4. Tanaka H, Takeuchi M, Takeda Y, Sakai S, Abe D, Ohwada C, et al. Identification of a novel TEL-Lyn fusion gene in primary myelofibrosis. Leukemia. 2010;24(Jan):197–200.

    Article  CAS  Google Scholar 

  5. Dai H-P, Yin J, Li Z, Yang C-X, Cao T, Chen P, et al. Rapid molecular response to dasatinib in a pediatric relapsed acute lymphoblastic leukemia with NCOR1-LYN Fusion. Front. Oncol. 2020;10:359.

  6. Piet Borst RE, Kool Marcel, Wijnholds Jan. A family of drug transporters: the multidrug resistence-associated proteins. J Natl Cancer Inst. 2000;92(16):1295–302.

    Article  Google Scholar 

  7. Guo Y, Shan Q, Gong Y, Lin J, Yang X, Zhou R. Oridonin in combination with imatinib exerts synergetic anti-leukemia effect in Ph+ acute lymphoblastic leukemia cells in vitro by inhibiting activation of LYN/mTOR signaling pathway. Cancer Biol Ther. 2012;13(13):1244–54.

    Article  CAS  Google Scholar 

  8. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–45.

    Article  CAS  Google Scholar 

  9. Yang K, Fu LW. Mechanisms of resistance to BCR-ABL TKIs and the therapeutic strategies: a review. Crit Rev Oncol Hematol. 2015;93(3):277–92.

    Article  Google Scholar 

  10. Patel AB, O’Hare T, Deininger MW. Mechanisms of resistance to ABL kinase inhibition in chronic myeloid leukemia and the development of next generation ABL kinase inhibitors. Hematol Oncol Clin North Am. 2017;31(4):589–612.

    Article  Google Scholar 

  11. Gotesman M, Vo TT, Herzog LO, Tea T, Mallya S, Tasian SK. et al. mTOR inhibition enhances efficacy of dasatinib in ABL-rearranged Ph-like ALL. Oncotarget. 2018;9(5):6562–71.

    Article  Google Scholar 

  12. Tasian SK, Teachey DT, Li Y, Shen F, Harvey RC, Chen IM, et al. Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2017;129(2):177–87.

    Article  CAS  Google Scholar 

  13. Feldhahn N, Arutyunyan A, Stoddart S, Zhang B, Schmidhuber S, Yi SJ, et al. Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia. Oncoimmunology. 2012;1(6):618–29.

    Article  Google Scholar 

  14. Delgado MD, Leon J. Myc roles in hematopoiesis and leukemia. Genes Cancer. 2010;1(Jun):605–16.

    Article  CAS  Google Scholar 

  15. Faber J, Krivtsov AV, Stubbs MC, Wright R, Davis TN, van den Heuvel-Eibrink M, et al. HOXA9 is required for survival in human MLL-rearranged acute leukemias. Blood. 2009;113(11):2375–85.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants-in-aid for scientific research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (17K10124 and 17K16277) and by Grant-in-Aid for Practical Research for Innovative Cancer Control (16ck0106066h0003, 17ck0106253h0001, 18ck0106253h0002, and 19ck0106253h0003).

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Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Toshihiro Tomii, Toshihiko Imamura, Azusa Mayumi & Hajime Hosoi

  2. Department of Pediatrics, Kyoto University, Kyoto, Japan

    Kuniaki Tanaka, Itaru Kato, Takashi Mikami & Junko Takita

  3. Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan

    Emi Soma

  4. Department of Pediatrics, Kyoto City Hospital, Kyoto, Japan

    Mio Yano

  5. Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan

    Kenichi Sakamoto

  6. Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Makiko Morita & Souichi Adachi

  7. Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan

    Nobutaka Kiyokawa

  8. Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Keizo Horibe

  9. Drug Discovery Technology Development Office, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

    Tatsutoshi Nakahata

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  1. Toshihiro Tomii
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Contributions

T.T. and T.I. designed studies and wrote the manuscript; T.T., T.I., A.M., E.S., M.Y., K.S., and N.K. performed genetic and in vitro functional studies; K.T., I.K., T.M., and M.M. performed in vivo studies using patient-derived xenograft model; K.H., S.A., T.N., J.T., and H.H. supervised research and participated in editing manuscript.

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Correspondence to Toshihiko Imamura.

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Tomii, T., Imamura, T., Tanaka, K. et al. Leukemic cells expressing NCOR1-LYN are sensitive to dasatinib in vivo in a patient-derived xenograft mouse model. Leukemia 35, 2092–2096 (2021). https://doi.org/10.1038/s41375-020-01091-3

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