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Dominant-negative type of IKZF1 deletion showed a favorable prognosis in adult B-cell acute lymphoblastic leukemia

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Abstract

IKZF1 deletion is a recurrent genomic alteration in B-cell acute lymphoblastic leukemia (B-ALL) and is divided into dominant-negative (DN) and loss of function (LOF) deletions. The prognostic impact of each deletion has not been fully elucidated. We retrospectively analyzed 117 patients with adult B-ALL including 60 patients with BCR::ABL1-positive B-ALL and 57 patients with BCR::ABL1-negative B-ALL by the fluorescence in situ hybridization (FISH) method for IKZF1 deletion and multiplex PCR for the 4 most common IKZF1 deletions (∆4–7, ∆2–7, ∆2–8, and ∆4–8). Samples, in which IKZF1 deletion was detected by FISH but a specific type of deletion was not identified by the PCR, were categorized as “other.” Patients were classified into a DN group that had at least 1 allele of ∆4–7 (n = 23), LOF and other group (n = 40), and wildtype group (n = 54). DN type IKZF1 deletions were found in 33.3% of BCR::ABL1-positive cases and 5.2% of BCR::ABL1-negative cases. LOF and other type IKZF1 deletions were found in 43.4% of BCR::ABL1-positive cases and 24.6% of BCR::ABL1-negative cases. Patients with the DN group showed significantly higher overall survival (OS) than that of the LOF and other and WT groups (P = 0.011). Multivariate analysis including age, WBC counts, complex karyotype, and DN type IKZF1 deletion showed that the DN type of IKZF1 deletion (HR = 0.22, P = 0.013) had a positive impact and age ≥ 65 (HR = 1.92, P = 0.029) had a negative impact on OS. The prognostic impact of IKZF1 deletion depends on the type of deletion and DN type of IKZF1 deletion showed better prognosis in adult B-ALL patients.

Clinical trial registration This study was part of a prospective observational study (Hokkaido Leukemia Net, UMIN000048611). It was conducted in compliance with ethical principles based on the Helsinki Declaration and was approved by the institutional review board of Hokkaido University Hospital (#015–0344).

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS), Grant-in-Aid for Young Scientists (B) (17K16174; K.O.), and Scientific Research (C) (16K09836; 20K08745; M.O.).

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Authors and Affiliations

  1. Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, 0608638, Japan

    Hiroyuki Kimura, Masahiro Onozawa, Shota Yoshida, Naoki Miyashita, Shota Yokoyama, Toshihiro Matsukawa, Hideki Goto, Tomoyuki Endo & Takanori Teshima

  2. Department of Pediatrics, Hokkaido University Hospital, Sapporo, Japan

    Shinsuke Hirabayashi

  3. Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital, Sapporo, Japan

    Hideki Goto, Satoshi Oguri, Shinichi Fujisawa & Takanori Teshima

  4. Blood Disorders Center, Aiiku Hospital, Sapporo, Japan

    Akio Mori & Takeshi Kondo

  5. Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan

    Daisuke Hidaka, Kohei Okada & Shuichi Ota

  6. Department of Hematology, Asahikawa City Hospital, Asahikawa, Japan

    Yasutaka Kakinoki

  7. Department of Hematology, Hakodate Municipal Hospital, Hakodate, Japan

    Yutaka Tsutsumi

  8. Department of Hematology, Sapporo City General Hospital, Sapporo, Japan

    Satoshi Yamamoto

  9. Department of Hematology, Kushiro Rosai Hospital, Kushiro, Japan

    Takuto Miyagishima

  10. Department of Internal Medicine, Kitami Red Cross Hospital, Kitami, Japan

    Junichi Hashiguchi & Takahiro Nagashima

  11. Department of Hematology, Sapporo Kosei General Hospital, Sapporo, Japan

    Makoto Ibata

  12. Department of Hematology, Obihiro Kosei Hospital, Obihiro, Japan

    Kentaro Wakasa

  13. Department of Hematology, Tonan Hospital, Sapporo, Japan

    Yoshihito Haseyama

  14. Department of Hematology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan

    Katsuya Fujimoto

  15. Department of Hematology, Kin-Ikyo Chuo Hospital, Sapporo, Japan

    Toshimichi Ishihara

  16. Department of Hematology, Teine Keijinkai Hospital, Sapporo, Japan

    Hajime Sakai

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  1. Hiroyuki Kimura
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Contributions

H.K. and M.O. designed the study, analyzed the data, and wrote the manuscript. J.H. developed FISH analysis and S.O. and S.F. performed FISH. S.Y., N.M., S.Y., T.M., S.H., H.G., and T.E. provided a critique of the manuscript. A.M., T.K., D.H., K.O., S.O., Y.K., Y.T., S.Y., T.M., J.H., T.N., M.I., K.W., Y.H., K.F., T.I., and H.S. recruited and treated the patients. T.T. revised and approved the manuscript. All authors contributed to the final version of the manuscript and approved it for publication.

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Correspondence to Masahiro Onozawa.

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Kimura, H., Onozawa, M., Yoshida, S. et al. Dominant-negative type of IKZF1 deletion showed a favorable prognosis in adult B-cell acute lymphoblastic leukemia. Ann Hematol 102, 3103–3113 (2023). https://doi.org/10.1007/s00277-023-05405-0

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