Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Allogeneic stem cell transplantation can prolong the survival of patients with NUP98-rearranged acute myeloid leukemia

Bone Marrow Transplantation volume 58, pages 1149–1151 (2023)Cite this article

Subjects

Translocation of nucleoporin 98kD (NUP98) located on chromosome 11p15 accounts for <1% of acute myeloid leukemia (AML) cases [1]. Fusions of NUP98 to more than 20 different partner genes have been described previously, including HOXA9, HOXA11 and NSD1 [2,3,4]. Translocation involving the NUP98 gene produces NUP98-fusion proteins and is associated with a poor prognosis in AML [2,3,4,5,6]. We here retrospectively present the clinical features and outcome of 13 patients with NUP98 rearrangement who underwent allogeneic stem cell transplantation (HSCT) in our center from December 2014 to March 2023. Seven patients were male, and six were female, with a median age of 33 years (range, 16–49) at transplant. All the patients were diagnosed with AML based on the 5th WHO classification. Six patients were with NUP98-HOXA9 fusion, One patient with NUP98-HOXA11fusion, and 6 patients with NUP98-NSD1 fusion. Five of the six patients with NUP98-NSD1 exhibit FLT3 internal tandem duplications (FLT3-ITD) mutation. Seven patients with NUP98-HOXA9 or NUP98-HOXA11fusion mostly bear a chromosome karyotype of t (7;11) (p15;p15). Of all the 13 patients, 1 patient has concurrent KMT2A mutation. Six patients had high expression of WT1 and another three patients had WT1 mutation on exon7 de novo. More detailed characteristics of patients are summarized in Table 1. All the patients received myeloablative HSCT. The conditioning regimens are as follows: six patients received condition consisting of 3.2 mg/kg  Bu (days -9 to -7), 40 mg/kg Cy (days -3 to -2), 2 g/m2Ara-c (days -6 to -4), and 30 mg/m2Flu or 5 mg/m2 Cladribine (days -6 to -4). One patient received 10 mg/m2 Idarubicin (days-6 to -4) and the same dose of Bu, Cy, Flu. Six patients with NUP98-NSD1 fusion all received a conditioning regimen consisting of 60 mg/m2 Melphalan(days-9 to -8), 5 mg/m2 Cladribine (days -7 to -5), 3.2 mg/kg  Bu (days -5 to -3), 30 mg/kg Cy (days -2 to -1), Patients received mismatched-sibling donor HSCT were added anti-T lymphocyte globulin (n = 9). Calcineurin protease inhibitors with or without mycophenolate mofetil were used to prevent graft versus host disease (GVHD). Donors with a median age of 37 years (range 12–57), seven of them were males and six were females. Of all the donors, three were matched siblings, nine were related haploidentical donors and one was matched unrelated donor (Table 1). Eight patients achieved complete remission (CR) after one induction chemotherapy, and one patient achieved CR after 2 cycles of chemotherapy. The other four patients with NUP98-NSD1 fusion never achieved CR before HSCT, of them two in partial response (PR) and two in non response (NR) before HSCT. Disease status at HSCT is shown in Table 1. All the patients received a median of 3 (range 2–7) cycles of chemotherapy prior to HSCT. On day 0, ten patients’ bone marrows show no minimal residual disease detected by flow cytometry or gene fusion detection. Three patients were with fusion gene positive on day 0, of whom two show 0% of blast cells and one exhibited 0.02% blast cells by flow cytometry. All the patients received peripheral stem cells infusion with a median positive CD34 count of 3.02 (range 1.34–11.14) × 106/kg. Median times to neutrophil and platelet recovery were 13 (range 10–20) and 16 (range 13–21) days, respectively. A total of three patients relapsed post allo-HSCT and only one patient is alive at the last follow up. The patient with NUP98-HOXA11 fusion gene relapsed 635 days post HSCT. After receiving multiple times of donor lymphocyte infusions (DLI), CD123 CART therapy, azacitidine, venetoclax and daratumumab, she presented with refractory disease and chose second HSCT from another donor and died soon. The patient relapsed 621 days post HSCT getting no response from DLI chose palliative care and died of leukemia. The patient relapsed 65 days post HSCT with concurrent FLT3-ITD mutation adopted Venetoclax and Gilteritinib therapy, she achieved CR with successive maintenance of these two drugs and developed chronic GVHD. She received DLI for a decline of chimerism assessed by short tandem repeats (STR) of the bone marrow. She is still alive to the last follow-up with cGVHD and in leukemia free survival (LFS) 477 days after HSCT. The incidence of II–IV aGVHD is 22.4%. Three patients died of non relapse mortality (NRM), two were due to severe infection, and one died because of uncontrolled acute gastrointestinal GVHD. The estimated 1 year NRM in patients with NUP98-NSD1 fusion gene and those with other fusion genes are 40% and 16.7%, respectively (p = 0.413). In all the patients, the estimated 3 year overall survival (OS) is 60.6%, the estimated 3 year LFS is 60.6%. Between patients with NUP98-NSD1 fusion gene and patients with other NUP98 fusion genes, the estimated 2 year OS is 60.0% and 66.7%, respectively, and the 2 year LFS is 60.0% and 66.7%, respectively. There is no statistical difference in OS or LFS between the two groups (p = 0.568).

Table 1 Transplant-related characteristics.
Full size table

Many researches [2, 3, 5, 7,8,9] indicate that AML with NUP98–HOXA9 fusion should be regarded as a poor prognostic group and NUP98-NSD1 has been reported in association with even more dismal prognosis, especially coexisting mutations of WT1 or FLT3 internal tandem duplications. A modified conditioning regimen containing melphalan, cladribine, busulfan and cyclophosphamide seems render CR and prolong the survival of patients with NUP98-NSD1. The four patients alive to the last follow-up are all accompanied by FLT3-ITD mutation and receive Gilteritinib post HSCT. In another word, patients with coexisting of NUP98-NSD1 and FLT3-ITD may get better survival than those without FLT-ITD mutation with the use of FLT3 inhibitors. Utilization of Bcl-2 inhibitors such as venetoclax seems effective but needs more evidence [10, 11]. In researches published recently [6, 12], KMT2A (also known as MLL1) is linked to the disease development of NUP98-HOXA9 induced leukemia and treatment with menin-MLL1 inhibition significantly prolongs survival of mice engrafted with NUP98-rearranged leukemias. In conclusion, with strong modified conditioning regimen and target drug therapy post HSCT, patients with NUP98 rearrangement may achieve CR and prolonged survival. Although the ultimate outcome of patients with NUP98 rearrangement still needs larger cohorts with longer follow-up, with the developing conditioning regimen and target drugs, the prolonged survival of these patients should be expected.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Romana SP, Radford-Weiss I, Ben Abdelali R, Schluth C, Petit A, Dastugue N, et al. NUP98 rearrangements in hematopoietic malignancies: a study of the Groupe Francophonede Cytogenetique Hematologique. Leukemia. 2006;20:696–706.6.

    Article  CAS  PubMed  Google Scholar 

  2. Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Zimmermann M, Peeters JK, Valk PJ, et al. NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood. 2011;118:3645–56. https://doi.org/10.1182/blood-2011-04-346643.

    Article  CAS  PubMed  Google Scholar 

  3. Ostronoff F, Othus M, Gerbing RB, Loken MR, Raimondi SC, Hirsch BA, et al. NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report. Blood. 2014;124:2400–7. https://doi.org/10.1182/blood-2014-04-570929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Michmerhuizen NL, Klco JM, Mullighan CG. Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies. Blood. 2020;136:2275–89. https://doi.org/10.1182/blood.2020007093.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chou W-C, Chen C-Y, Hou H-A, Lin L-I, Tang J-L, Yao M, et al. Acute myeloid leukemia bearing t(7;11)(p15;p15) is a distinct cytogenetic entity with poor outcome and a distinct mutation profile: comparative analysis of 493 adult patients. Leukemia. 2009;23:1303–10. https://doi.org/10.1038/leu.2009.25.

    Article  CAS  PubMed  Google Scholar 

  6. Shima Y, Yumoto M, Katsumoto T, Kitabayashi I. MLL is essential for NUP98-HOXA9-induced leukemia. Leukemia. 2017;31:2200–10. https://doi.org/10.1038/leu.2017.62.

    Article  CAS  PubMed  Google Scholar 

  7. Niktoreh N, Walter C, Zimmermann M, von Neuhoff C, von Neuhoff N, Rasche M, et al. Mutated WT1, FLT3-ITD, and NUP98-NSD1 fusion in various combinations define a poor prognostic group in pediatric acute myeloid leukemia. J Oncol. 2019;2019:1609128. https://doi.org/10.1155/2019/1609128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K, et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet. 1996;12:154–8. https://doi.org/10.1038/ng0296-154.

    Article  CAS  PubMed  Google Scholar 

  9. Moore MA, Chung KY, Plasilova M, Schuringa JJ, Shieh JH, Zhou P, et al. NUP98dysregulation in myeloid leukemogenesis. Ann NY Acad Sci. 2007;1106:114–42.

    Article  CAS  PubMed  Google Scholar 

  10. Sun H, Yan H, Yan Z, Zhu Y, Yang G, Zhang S. Acute myeloid leukemia patients with NUP98::NSD1 showing initially poor treatment response can benefit from FLT3 inhibitors and venetoclax as well as HSCT. Ann Hematol. 2023;102:473–5. https://doi.org/10.1007/s00277-022-05047-8.

    Article  CAS  PubMed  Google Scholar 

  11. Kivioja JL, Thanasopoulou A, Kumar A, Kontro M, Yadav B, Majumder MM, et al. Dasatinib and navitoclax act synergistically to target NUP98-NSD1+/FLT3-ITD+ acute myeloid leukemia. Leukemia. 2019;33:1360–72. https://doi.org/10.1038/s41375-018-0327-2.

    Article  CAS  PubMed  Google Scholar 

  12. Heikamp EB, Henrich JA, Perner F, Wong EM, Hatton C, Wen Y, et al. The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML. Blood. 2022;139:894–906. https://doi.org/10.1182/blood.2021012806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work is supported by Tianjin Municipal Science and Technology Commission Grant (21JCZDJC01170), Chinese Academy of Medical Sciences Innovation fund for Medical Sciences (2021-I2M-C&T-B-080, 2021-I2M-1-017), Haihe Laboratory of Cell Ecosystem Innovation Fund(22HHXBSS00036) to SF, Youth Program of National Natural Science Foundation of China 81900182) to YS.

Author information

Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

    Yuyan Shen, Tingting Zhang, Lining Zhang, Sisi Zhen, Zhangjie Chen, Rongli Zhang, Donglin Yang, Jialin Wei, Yi He, Erlie Jiang & Sizhou Feng

  2. Tianjin Institutes of Health Science, Tianjin, China

    Yuyan Shen, Tingting Zhang, Lining Zhang, Sisi Zhen, Zhangjie Chen, Rongli Zhang, Donglin Yang, Jialin Wei, Yi He, Erlie Jiang & Sizhou Feng

Authors
  1. Yuyan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tingting Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lining Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sisi Zhen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhangjie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rongli Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Donglin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jialin Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yi He
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Erlie Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sizhou Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YS participated in data collection and manuscript writing. TZ, LZ, SZ, ZC collected the data. RL, JW, DY, EJ, SF, YH contributed to treating patients and supervised the study. YH and SF designed and approved the study.

Corresponding authors

Correspondence to Yi He or Sizhou Feng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shen, Y., Zhang, T., Zhang, L. et al. Allogeneic stem cell transplantation can prolong the survival of patients with NUP98-rearranged acute myeloid leukemia. Bone Marrow Transplant 58, 1149–1151 (2023). https://doi.org/10.1038/s41409-023-02030-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-023-02030-3

This article is cited by

Search

Advanced search

Quick links