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High WT1 mRNA expression after induction chemotherapy and FLT3-ITD have prognostic impact in pediatric acute myeloid leukemia: a study of the Japanese Childhood AML Cooperative Study Group

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Abstract

The prognostic value of WT1 mRNA expression in pediatric acute myeloid leukemia (AML) remains controversial. A sample of newly diagnosed (n = 158) AML patients from the Japanese Childhood AML Cooperative Treatment Protocol, AML 99, were simultaneously analyzed for WT1 expression, cytogenetic abnormalities and gene alterations (FLT3, KIT, MLL, and RAS). WT1 expression (including more than 2,500 copies/μgRNA) was detected in 122 of the 158 (77.8 %) initial diagnostic AML bone marrow samples (median 45,500 copies/μgRNA). Higher WT1 expression was detected in French American British (FAB)-M0, M3, M7 and lower expression in M4 and M5. Higher WT1 expression was detected in AML with inv(16), t(15;17) and Down syndrome and lower in AML with 11q23 abnormalities. Multivariate analyses demonstrated that FLT3-internal tandem duplication (ITD), KIT mutation, MLL-partial tandem duplication were correlated with poor prognosis; however, higher WT1 expression was not. FLT3-ITD was correlated with WT1 expression and prognosis. Furthermore, 74 WT1 expression after induction chemotherapy was analyzed. Higher WT1 expression after induction chemotherapy was significantly correlated with M1 or M2/M3 marrow, FLT3-ITD and poor prognosis. Multivariate analyses in 74 AML patients revealed that FLT3-ITD, MLL-PTD, and KIT mutations were associated with poor prognosis; however, NRAS Mutation, KRAS mutation and high WT1 expression (>10,000 copies/μgRNA) did not show poor prognosis. Our findings suggest that higher WT1 expression at diagnosis does not correlate with poor prognosis, but that WT1 expression after induction chemotherapy is considered to be a useful predictor of clinical outcome in pediatric AML.

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Acknowledgements

We would like to express our appreciation to all the doctors for their participation in the Japanese Childhood AML Cooperative Study Group.

Author information

Authors and Affiliations

  1. Department of Hematology/Oncology, Gunma Children’s Medical Center, 779 Shimohakoda, Hokkitsu, Shibukawa, Gunma, 377-8577, Japan

    Akira Shimada & Yasuhide Hayashi

  2. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Akira Shimada & Seiji Kojima

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

    Tomohiko Taki

  4. Department of Research and Development Diagnostic Division, Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan

    Daisuke Koga

  5. Division of Pediatrics, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 18-22, Honkomagome 3 chome, Bunkyo-ku, Tokyo, Japan

    Ken Tabuchi

  6. Department of Pediatrics, National Hospital Organization Osaka National Hospital, Osaka, Japan

    Akio Tawa

  7. Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan

    Ryoji Hanada

  8. Department of Pediatric Hematology/Oncology, Ibaraki Children’s Hospital, Ibaraki, Japan

    Masahiro Tsuchida

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

    Keizo Horibe

  10. First Department of Pediatrics, Toho University School of Medicine, Tokyo, Japan

    Ichiro Tsukimoto

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

    Souichi Adachi

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  1. Akira Shimada
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Correspondence to Yasuhide Hayashi.

Additional information

Supported in part by a Grant-in-Aid for Cancer Research and a grant for Clinical Cancer Research and Research on Children and Families from the Ministry of Health, Labor and Welfare of Japan, and by a research grant for Gunma Prefectural Hospitals.

Electronic supplementary material

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12185_2012_1163_MOESM1_ESM.doc

Supplemental Figure 1. WT1 mRNA expression in 158 AML patients at time of initial diagnosis and 28 normal controls. A total of 122 out of 158 (77.8%) AML patients expressed more than the cut-off value of 2,500 copies/μgRNA. (DOC 40 kb)

12185_2012_1163_MOESM2_ESM.doc

Supplemental Figure 2. WT1 mRNA expression in 74 AML patients except for t(15;17) and Down syndrome at initial diagnosis and after 1st induction chemotherapy. A total of 58 out of 74 (78.4%) patients were WT1-positive at time of diagnosis (median, 18,000 μg/RNA) and 11 out of 74 (14.9%) still remained WT1-positive after induction chemotherapy (median, 215 μg/RNA). (DOC 45 kb)

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Shimada, A., Taki, T., Koga, D. et al. High WT1 mRNA expression after induction chemotherapy and FLT3-ITD have prognostic impact in pediatric acute myeloid leukemia: a study of the Japanese Childhood AML Cooperative Study Group. Int J Hematol 96, 469–476 (2012). https://doi.org/10.1007/s12185-012-1163-1

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