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High frequencies of simultaneous FLT3-ITD, WT1 and KIT mutations in hematological malignancies with NUP98-fusion genes

Leukemia volume 24, pages 1975–1977 (2010)Cite this article

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Acute myeloid leukemia (AML) is heterogeneous in clinical features and molecular pathogenesis. Cooperating alterations of several genes, including oncogenes or tumor suppressor genes, lead to AML development.1 AML leukemogenesis is thought to require at least two different types of genetic change: class I mutations, which confer a proliferative or survival advantage; and class II mutations, which block myeloid differentiation and provide self-renewability.1 In hematological malignancies with 11p15 translocations, the nucleoporin (NUP) 98 gene is reportedly fused to various partner genes, often including homeobox genes, such as HOXA9, A11, A13, C11, C13, D11, D13 and PMX1.2 With respect to the oncogenic mechanism of NUP98-HOX fusion proteins, a previous study using a murine bone marrow transplantation assay revealed that NUP98-HOXA9, -HOXD13 and -PMX1 fusion proteins induce myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN), which progress to AML.2 This latency period indicates that additional genetic events might be required for leukemic transformation. Therefore, we examined somatic mutations of the FLT3, KIT, WT1, RUNX1, CEBPA, NPM1, NRAS, KRAS and MLL genes, which are prevalent in AML, in leukemia patients with NUP98 fusion genes. This study was approved by local ethical committee.

Sixteen patients with chromosomal 11p15 translocations included nine with NUP98-HOXA9, two with NUP98-HOXA13, two with NUP98-HOXA11 and one each with NUP98-HOXC11, NUP98-HOXD11, NUP98-HOXD13 or NUP98-NSD3 (Table 1). The partner gene fused to NUP98 could not be detected in one patient with t(4;11)(q21;p15); however, fluorescent in situ hybridization analysis using a probe containing NUP98 showed split signals (data not shown). No patients had any additional chromosomal abnormality except for chromosomal 11p15 translocations (Supplementary data). Two patients with t(7;11)(p15;p15) had double NUP98 fusion transcripts: patient (PN) 13 had simultaneous NUP98-HOXA9 and NUP98-HOXA13 fusions, and PN14 had simultaneous NUP98-HOXA9 and NUP98-HOXA11 fusions. In all, 15 of the 16 patients with NUP98-related hematological malignancies were diagnosed as having myeloid malignancies, and the other patient (PN16) were initially diagnosed as having T-cell non-Hodgkin's lymphoma with t(4;11)(q21;p15), and transformed into acute myelomonocytic leukemia with the same t(4;11) (lineage switch). Patients with myeloid malignancies consisted of 10 patients with AML, 2 patients with MDS and 3 patients with MPN.

Table 1 Clinical features and additional mutations of patients with NUP98-related leukemias
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Acknowledgements

This work was supported by a Grant-in-Aid for Cancer Research, Research on Children and Families, Research on intractable diseases, Health and Labor Sciences Research Grants from the Ministry of Health, Labor and Welfare of Japan, and by Grants-in-Aid for Scientific Research (B, C) or Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We thank Drs Ryoji Hanada (Division of Hematology/Oncology, Saitama Children's Medical Center, Japan), Kazuko Hamamoto (Department of Pediatrics, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Japan), Hideo Nakamura (Department of Internal Medicine, Koufudai Hospital, Nagasaki, Japan), Kazuma Ohyashiki (First Department of Internal Medicine, Division of Hematology, Tokyo Medical University, Japan), Ikuo Miura, Department of Internal Medicine (Division of Hematology and Oncology, St Marianna University School of Medicine, Japan), Keiki Kawakami (Division of Hematology, Suzuka General Hospital, Japan), Hiroshi Miwa (Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, Japan), Takaharu Matsuyama (Division of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Japan) and Yasuhito Arai, PhD (Cancer Genome Project, National Cancer Center Research Institute, Tokyo, Japan) for providing samples and clinical data of patients with chromosomal 11p15 translocations. We also thank Mrs Shoko Sohma, Hisae Soga, Midori Furui, Mayumi Naito, Mayumi Nagase and Rie Eda for their excellent technical assistance.

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Authors and Affiliations

  1. Division of Blood Transfusion, Shimane University Hospital, Shimane, Japan

    T Taketani

  2. Department of Pediatrics, Shimane University School of Medicine, Shimane, Japan

    T Taketani, S Fukuda & S Yamaguchi

  3. Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan

    T Taki

  4. Department of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

    T Nakamura

  5. Hematology Division, National Cancer Center Hospital, Tokyo, Japan

    Y Kobayashi

  6. Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    E Ito

  7. Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan. E-mail: hayashiy-tky@umin.ac.jp,

    Y Hayashi

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Taketani, T., Taki, T., Nakamura, T. et al. High frequencies of simultaneous FLT3-ITD, WT1 and KIT mutations in hematological malignancies with NUP98-fusion genes. Leukemia 24, 1975–1977 (2010). https://doi.org/10.1038/leu.2010.207

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