Skip to main content

Advertisement

SpringerLink
Log in

Functional analysis of a novel fusion protein PAX5-KIDINS220 identified in a pediatric Ph-like ALL patient

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

PAX5-KIDINS220 (PAX5-K220) is a novel chimeric fusion gene identified in a pediatric Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) patient, but the function of the encoded fusion protein has not yet been analyzed. Here, we report the functional analysis of PAX5-K220 in vitro. We successfully generated PAX5-K220 expressing cells and demonstrate that PAX5-K220 is a nuclear protein. Luciferase reporter assay reveals that PAX5-K220 inhibits wild-type PAX5 transcriptional activity in a dominant-negative fashion like other PAX5-related fusion proteins, and may contribute to lymphocyte differentiation block. However, although identified in Ph-like ALL, PAX5-K220 does not induce IL-3-independent proliferation when transduced in the IL-3-dependent Ba/F3 murine leukemia cells, but rather attenuates growth. These results reveal that PAX5-K220 certainly shares the character with other PAX5-related fusion proteins rather than other fusion proteins with tyrosine kinase activity identified in Ph-like ALL, and did not contribute to proliferation activity. Precise functional analysis of each differently partnered PAX5 fusion protein is warranted in the future for better understanding of PAX5-related translocations and their effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Coyaud E, Struski S, Prade N, Familiades J, Eichner R, Quelen C, et al. Wide diversity of PAX5 alterations in B-ALL: a groupe francophone de cytogenetique hematologique study. Blood. 2010;115(15):3089–97.

    Article  CAS  Google Scholar 

  2. Nebral K, Denk D, Attarbaschi A, Konig M, Mann G, Haas OA, et al. Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. Leukemia. 2009;23(1):134–43.

    Article  CAS  Google Scholar 

  3. Bousquet M, Broccardo C, Quelen C, Meggetto F, Kuhlein E, Delsol G, et al. A novel PAX5-ELN fusion protein identified in B-cell acute lymphoblastic leukemia acts as a dominant negative on wild-type PAX5. Blood. 2007;109(8):3417–23.

    Article  CAS  Google Scholar 

  4. Fazio G, Palmi C, Rolink A, Biondi A, Cazzaniga G. PAX5/TEL acts as a transcriptional repressor causing down-modulation of CD19, enhances migration to CXCL12, and confers survival advantage in pre-BI cells. Cancer Res. 2008;68(1):181–9.

    Article  CAS  Google Scholar 

  5. Kawamata N, Pennella MA, Woo JL, Berk AJ, Koeffler HP. Dominant-negative mechanism of leukemogenic PAX5 fusions. Oncogene. 2012;31(8):966–77.

    Article  CAS  Google Scholar 

  6. Kurahashi S, Hayakawa F, Miyata Y, Yasuda T, Minami Y, Tsuzuki S, et al. PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML. Oncogene. 2011;30(15):1822–30.

    Article  CAS  Google Scholar 

  7. Schinnerl D, Fortschegger K, Kauer M, Marchante JR, Kofler R, Den Boer ML, et al. The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia. Blood. 2015;125(8):1282–91.

    Article  CAS  Google Scholar 

  8. Sakamoto K, Imamura T, Kanayama T, Yano M, Asai D, Deguchi T, et al. Ph-like acute lymphoblastic leukemia with a novel PAX5-KIDINS220 fusion transcript. Genes Chromosomes Cancer. 2017;56(4):278–84.

    Article  CAS  Google Scholar 

  9. Iglesias T, Cabrera-Poch N, Mitchell MP, Naven TJ, Rozengurt E, Schiavo G. Identification and cloning of Kidins220, a novel neuronal substrate of protein kinase D. J Biol Chem. 2000;275(51):40048–56.

    Article  CAS  Google Scholar 

  10. Arevalo JC, Yano H, Teng KK, Chao MV. A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein. EMBO J. 2004;23(12):2358–68.

    Article  CAS  Google Scholar 

  11. McNiece IK, Bradley TR, Kriegler AB, Hodgson GS. A growth factor produced by WEHI-3 cells for murine high proliferative potential GM-progenitor colony forming cells. Cell Biol Int Rep. 1982;6(3):243–51.

    Article  CAS  Google Scholar 

  12. Morita S, Kojima T, Kitamura T. Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 2000;7(12):1063–6.

    Article  CAS  Google Scholar 

  13. Fujiki A, Imamura T, Sakamoto K, Kawashima S, Yoshida H, Hirashima Y, et al. All-trans retinoic acid combined with 5-Aza-2’-deoxycytidine induces C/EBPalpha expression and growth inhibition in MLL-AF9-positive leukemic cells. Biochem Biophys Res Commun. 2012;428(2):216–23.

    Article  CAS  Google Scholar 

  14. Yoshida H, Imamura T, Fujiki A, Hirashima Y, Miyachi M, Inukai T, et al. Post-transcriptional modulation of C/EBPalpha prompts monocytic differentiation and apoptosis in acute myelomonocytic leukaemia cells. Leuk Res. 2012;36(6):735–41.

    Article  CAS  Google Scholar 

  15. Tomii T, Imamura T, Yano M, Sakamoto K, Kato I, Tanaka K, et al. Leukemic cell expressing a novel kinase fusion protein NCOR1-LYN exhibits high sensitivity to Dasatinib and Rapamycin. Blood. 2018;132(Supplement 1):1557–1557.

    Article  Google Scholar 

  16. Gu Z, Churchman ML, Roberts KG, Moore I, Zhou X, Nakitandwe J, et al. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nat Genet. 2019;51(2):296–307.

    Article  CAS  Google Scholar 

  17. Liang X, Gu J, Li T, Zhao L, Fu X, Zhang W, et al. PAX5 haploinsufficiency induce cancer cell dormancy in Raji cells. Exp Cell Res. 2018;367:30–6.

    Article  CAS  Google Scholar 

  18. Jamrog L, Chemin G, Fregona V, Coster L, Pasquet M, Oudinet C, et al. PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice. Proc Natl Acad Sci USA. 2018;115(41):10357–62.

    Article  CAS  Google Scholar 

  19. Smeenk L, Fischer M, Jurado S, Jaritz M, Azaryan A, Werner B, et al. Molecular role of the PAX5-ETV6 oncoprotein in promoting B-cell acute lymphoblastic leukemia. EMBO J. 2017;36(6):718–35.

    Article  CAS  Google Scholar 

  20. Ebinger S, Ozdemir EZ, Ziegenhain C, Tiedt S, Castro Alves C, Grunert M, et al. Characterization of rare, dormant, and therapy-resistant cells in acute lymphoblastic leukemia. Cancer Cell. 2016;30(6):849–62.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by grants-in-aid for scientific research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (17K10124) and a grant from the Japan Agency for Medical Research and Development (17ck0106253h0001).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Takuyo Kanayama, Toshihiko Imamura, Azusa Mayumi, Kenichi Sakamoto & Hajime Hosoi

  2. Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan

    Emi Soma

  3. Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan

    Kenichi Sakamoto

  4. Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Fumihiko Hayakawa

  5. Department of Human Resource Development for Cancer, Faculty of Medical Sciences, University of Fukui, Fukui, Japan

    Akihiko Tanizawa

  6. Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan

    Nobutaka Kiyokawa

Authors
  1. Takuyo Kanayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshihiko Imamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Azusa Mayumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emi Soma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenichi Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fumihiko Hayakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akihiko Tanizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nobutaka Kiyokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hajime Hosoi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshihiko Imamura.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Additional information

Publisher's Note

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

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kanayama, T., Imamura, T., Mayumi, A. et al. Functional analysis of a novel fusion protein PAX5-KIDINS220 identified in a pediatric Ph-like ALL patient. Int J Hematol 112, 714–719 (2020). https://doi.org/10.1007/s12185-020-02944-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-020-02944-4

Keywords

Search

Navigation