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Direct binding of Grb2 has an important role in the development of myeloproliferative disease induced by ETV6/FLT3

Leukemia volume 27, pages 1433–1436 (2013)Cite this article

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FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in hematological malignancies.1 The most common mutations of FLT3 are internal tandem duplications (ITDs) within the juxtamembrane domain, which occur in 20% to 30% of patients with acute myeloid leukemia (AML).2, 3 Although FLT3 is a potential therapeutic target in AML, recent studies involving FLT3 inhibitors as single agents in patients with AML showed limited clinical responses.4 FLT3 has been reported to fuse to ETV6 (TEL) in a few cases of myeloid/lymphoid neoplasms with eosinophilia (MLN-eo) carrying a translocation t(12;13)(p13;q12).5, 6 Although it has been shown that ETV6/FLT3 acts as a constitutively active tyrosine kinase, the molecular mechanisms underlying ETV6/FLT3-mediated leukemogenesis remain incompletely understood.7, 8, 9

Previous studies have shown that FLT3-ITDs induce a lethal MPD in mice and that tyrosine residues 589 and 591 in the juxtamembrane domain of FLT3 are critical for STAT5 phosphorylation and generation of the MPD phenotype.10 We also demonstrated the corresponding results for FLT3-ITD in our murine BMT experiment (Supplementary Figures S3A and B). On the other hand, mice that received the double tyrosine-to-phenylalanine mutant of E/F-1 at sites 589 and 591 (Y589/591F) in the juxtamembrane domain of FLT3 developed a similar MPD (Supplementary Table S1). There was no significant difference in survival between recipients of E/F-1 vs Y589/591F, with both mice groups succumbing to a fatal MPD within a median survival time of 18 and 19.5 days, respectively (P=0.284; Figure 1C). The Y589/591F mutation did not abrogate STAT5, Erk1/2 and Akt activation in Ba/F3 cells transformed by E/F-1 (Supplementary Figure S4), which is consistent with the previous studies using a deletion mutant of the FLT3 juxtamembrane domain in ETV6/FLT3.9

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Acknowledgements

This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MH).

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Authors and Affiliations

  1. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    K Chonabayashi, M Hishizawa, Y Nagai, T Ishikawa, T Uchiyama & A Takaori-Kondo

  2. Foundation for Biomedical Research and Innovation, Kobe, Japan

    S Kawamata

  3. Division of Hematology and Immunology, Department of Internal Medicine, Ohtsu Red Cross Hospital, Ohtsu, Japan

    T Ohno

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  1. K Chonabayashi
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Correspondence to M Hishizawa.

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Chonabayashi, K., Hishizawa, M., Kawamata, S. et al. Direct binding of Grb2 has an important role in the development of myeloproliferative disease induced by ETV6/FLT3. Leukemia 27, 1433–1436 (2013). https://doi.org/10.1038/leu.2012.333

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