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ACUTE MYELOID LEUKEMIA

Immunoglobulin superfamily member 8 maintains myeloid leukemia stem cells through inhibition of β-catenin degradation

Leukemia volume 36, pages 1550–1562 (2022)Cite this article

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Abstract

The identification of characteristic differences between cancer stem cells and their normal counterparts remains a key challenge for cancer treatment. Here, we investigated the role of immunoglobulin superfamily member 8 (Igsf8, also known as EWI-2, PGRL, and CD316) on normal and malignant hematopoietic stem cells, mainly using the conditional knockout model. Deletion of Igsf8 did not affect steady state hematopoiesis, but it led to a significant improvement of survival in mouse myeloid leukemia models. Deletion of Igsf8 significantly depletes leukemia stem cells (LSCs) through enhanced apoptosis and β-catenin degradation. At a molecular level, we found that activation of β-catenin in LSCs depends on Igsf8, which promotes the association of FZD4 with its co-receptor LRP6 in the presence of Igsf8. Similarly, IGSF8 inhibition blocks the colony-forming ability of LSCs and improves the survival of recipients in xenograft models of myeloid leukemia. Collectively, these data indicate strong genetic evidence identifying Igsf8 as a key regulator of myeloid leukemia and the possibility that targeting IGSF8 may serve as a new therapeutic approach against myeloid leukemia.

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Fig. 1: Igsf8 is dispensable in steady-state hematopoiesis.
Fig. 2: Igsf8 deletion impairs initiation and propagation of myeloid leukemia.
Fig. 3: Igsf8 deletion depletes leukemia stem cells and leads to increased apoptosis.
Fig. 4: IGSF8 is required for human myeloid leukemia.
Fig. 5: Igsf8 deletion downregulates the β-catenin pathway in myeloid leukemia.
Fig. 6: Igsf8 deletion led to an increase of phosphorylated β-catenin through impaired FZD4-LRP6 receptor interaction in myeloid leukemia.

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References

  1. Clarke MF. Clinical and therapeutic implications of cancer stem cells. N Engl J Med. 2019;380:2237–45.

    Article  CAS  Google Scholar 

  2. Lytle NK, Barber AG, Reya T. Stem cell fate in cancer growth, progression and therapy resistance. Nat Rev Cancer. 2018;18:669–80.

    Article  CAS  Google Scholar 

  3. Krause DS, Van Etten RA. Right on target: Eradicating leukemic stem cells. Trends Mol Med. 2007;13:470–81.

    Article  CAS  Google Scholar 

  4. Hemler ME. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol. 2005;6:801–11.

    Article  CAS  Google Scholar 

  5. Yáñez-Mó M, Barreiro O, Gordon-Alonso M, Sala-Valdés M, Sánchez-Madrid F. Tetraspanin-enriched microdomains: a functional unit in cell plasma membranes. Trends Cell Biol. 2009;19:434–46.

    Article  Google Scholar 

  6. Charrin S, Jouannet S, Boucheix C, Rubinstein E. Tetraspanins at a glance. J Cell Sci. 2014;127:3641–8.

    CAS  PubMed  Google Scholar 

  7. Wang HX, Li Q, Sharma C, Knoblich K, Hemler ME. Tetraspanin protein contributions to cancer. Biochem Soc Trans. 2011;39:547–52.

    Article  CAS  Google Scholar 

  8. Hemler ME. Tetraspanin proteins promote multiple cancer stages. Nat Rev Cancer. 2014;14:49–60.

    Article  CAS  Google Scholar 

  9. Lapalombella R, Yeh YY, Wang L, Ramanunni A, Rafiq S, Jha S, et al. Tetraspanin CD37 directly mediates transduction of survival and apoptotic signals. Cancer Cell. 2012;21:694–708.

    Article  CAS  Google Scholar 

  10. Kwon HY, Bajaj J, Ito T, Blevins A, Konuma T, Weeks J, et al. Tetraspanin 3 is required for the development and propagation of acute myelogenous leukemia. Cell Stem Cell. 2015;17:152–64.

    Article  CAS  Google Scholar 

  11. Stipp CS, Kolesnikova TV, Hemler ME. EWI-2 is a major CD9 and CD81 partner and member of a novel Ig protein subfamily. J Biol Chem. 2001;276:40545–54.

    Article  CAS  Google Scholar 

  12. Clark KL, Zeng Z, Langford AL, Bowen SM, Todd SC. PGRL is a major CD81-associated protein on lymphocytes and distinguishes a new family of cell surface proteins. J Immunol. 2001;167:5115–21.

    Article  CAS  Google Scholar 

  13. Charrin S, Le Naour F, Labas V, Billard M, Le Caer JP, Emile JF, et al. EWI-2 is a new component of the tetraspanin web in hepatocytes and lymphoid cells. Biochem J. 2003;373:409–21.

    Article  CAS  Google Scholar 

  14. Umeda R, Satouh Y, Takemoto M, Nakada-Nakura Y, Liu K, Yokoyama T, et al. Structural insights into tetraspanin CD9 function. Nat Commun. 2020;11:1606.

    Article  CAS  Google Scholar 

  15. Stipp CS, Kolesnikova TV, Hemler ME. EWI-2 regulates alpha3beta1 integrin-dependent cell functions on laminin-5. J Cell Biol. 2003;163:1167–77.

    Article  CAS  Google Scholar 

  16. Kolesnikova TV, Stipp CS, Rao RM, Lane WS, Luscinskas FW, Hemler ME. EWI-2 modulates lymphocyte integrin alpha4beta1 functions. Blood 2004;103:3013–9.

    Article  CAS  Google Scholar 

  17. Kettner S, Kalthoff F, Graf P, Priller E, Kricek F, Lindley I, et al. EWI-2/CD316 is an inducible receptor of HSPA8 on human dendritic cells. Mol Cell Biol. 2007;27:7718–26.

    Article  CAS  Google Scholar 

  18. Wang HX, Sharma C, Knoblich K, Granter SR, Hemler ME. EWI-2 negatively regulates TGF-β signaling leading to altered melanoma growth and metastasis. Cell Res. 2015;25:370–85.

    Article  CAS  Google Scholar 

  19. Kolesnikova TV, Kazarov AR, Lemieux ME, Lafleur MA, Kesari S, Kung AL, et al. Glioblastoma inhibition by cell surface immunoglobulin protein EWI-2, in vitro and in vivo. Neoplasia 2009;11:77–86.

    Article  CAS  Google Scholar 

  20. Zhang XA, Lane WS, Charrin S, Rubinstein E, Liu L. EWI2/PGRL associates with the metastasis suppressor KAI1/CD82 and inhibits the migration of prostate cancer cells. Cancer Res. 2003;63:2665–74.

    CAS  PubMed  Google Scholar 

  21. Fu C, Zhang Q, Wang A, Yang S, Jiang Y, Bai L, et al. EWI-2 controls nucleocytoplasmic shuttling of EGFR signaling molecules and miRNA sorting in exosomes to inhibit prostate cancer cell metastasis. Mol Oncol. 2021;15:1543–65.

    Article  Google Scholar 

  22. Inoue N, Nishikawa T, Ikawa M, Okabe M. Tetraspanin-interacting protein IGSF8 is dispensable for mouse fertility. Fertil Steril. 2012;98:465–70.

    Article  CAS  Google Scholar 

  23. Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE, et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 2010;466:765–8.

    Article  CAS  Google Scholar 

  24. Bajaj J, Konuma T, Lytle NK, Kwon HY, Ablack JN, Cantor JM, et al. CD98-mediated adhesive signaling enables the establishment and propagation of acute myelogenous leukemia. Cancer Cell. 2016;30:792–805.

    Article  CAS  Google Scholar 

  25. Hattori A, Tsunoda M, Konuma T, Kobayashi M, Nagy T, Glushka J, et al. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature 2017;545:500–4.

    Article  CAS  Google Scholar 

  26. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011;478:524–8.

    Article  CAS  Google Scholar 

  27. Somervaille TC, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006;10:257–68.

    Article  CAS  Google Scholar 

  28. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl J Med. 2004;351:657–67.

    Article  CAS  Google Scholar 

  29. Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12:528–41.

    Article  CAS  Google Scholar 

  30. Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010;327:1650–3.

    Article  CAS  Google Scholar 

  31. Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D, et al. β-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell. 2010;18:606–18.

    Article  CAS  Google Scholar 

  32. Heidel FH, Bullinger L, Feng Z, Wang Z, Neff TA, Stein L, et al. Genetic and pharmacologic inhibition of β-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem Cell. 2012;10:412–24.

    Article  CAS  Google Scholar 

  33. Kolligs FT, Hu G, Dang CV, Fearon ER. Neoplastic transformation of RK3E by mutant beta-catenin requires deregulation of Tcf/Lef transcription but not activation of c-myc expression. Mol Cell Biol. 1999;19:5696–706.

    Article  CAS  Google Scholar 

  34. Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 2017;169:985–99.

    Article  CAS  Google Scholar 

  35. Bugter JM, Fenderico N, Maurice MM. Mutations and mechanisms of WNT pathway tumour suppressors in cancer. Nat Rev Cancer. 2021;21:5–21.

    Article  CAS  Google Scholar 

  36. Chairoungdua A, Smith DL, Pochard P, Hull M, Caplan MJ. Exosome release of β-catenin: A novel mechanism that antagonizes Wnt signaling. J Cell Biol. 2010;190:1079–91.

    Article  CAS  Google Scholar 

  37. Lento W, Ito T, Zhao C, Harris JR, Huang W, Jiang C, et al. Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration. Genes Dev. 2014;28:995–1004.

    Article  CAS  Google Scholar 

  38. van Spriel AB, de Keijzer S, van der Schaaf A, Gartlan KH, Sofi M, Light A, et al. The tetraspanin CD37 orchestrates the α(4)β(1) integrin-Akt signaling axis and supports long-lived plasma cell survival. Sci Signal. 2012;5:ra82.

    PubMed  Google Scholar 

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Acknowledgements

We thank the lab members in Division of Molecular Therapy and FACS Core Laboratory (The Institute of Medical Science, The University of Tokyo) for helpful support and comments. We would like to thank Naokazu Inoue (Fukushima Medical University) for the Igsf8flox/flox mice line, Toshio Kitamura (The Institute of Medical Science, The University of Tokyo) for the pMYs-IRES-GFP vector, and Susumu Goyama (University of Tokyo) for the human β-CATENIN construct. Igsf8flox/flox mice (strain: B6D2;129S2-Igsf8 < tm1.1Osb > ; RBRC05637) were provided by the RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan. This research was funded by the SGH foundation, the Japanese Society of Hematology Research Grant, the Princess Takamatsu Cancer Research Fund, and the Cooperative Research Program (Joint Usage/Research Center program) of Institute for Frontier Life and Medical Sciences, Kyoto University. This research was also supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (20K08748 to TK; 20J10521 to KJ; 19H05746 to AI). KJ is also supported by a doctoral course fellowship from the JSPS.

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Authors and Affiliations

  1. Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Koji Jimbo, Yasuhito Nannya & Takaaki Konuma

  2. Division of Molecular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Koji Jimbo & Arinobu Tojo

  3. Division of Stem Cell and Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Koji Jimbo, Yaeko Nakajima-Takagi, Shuhei Koide & Atsushi Iwama

  4. Laboratory of Cell Fate Dynamics and Therapeutics, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan

    Takahiro Ito

  5. Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yasuhito Nannya, Arinobu Tojo & Takaaki Konuma

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  1. Koji Jimbo
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Contributions

KJ performed the majority of experiments, analyzed the data, and contributed to the writing the paper. YNT performed the RNA sequencing analysis. SK supported the data of immunofluorescence staining. YN, and AI wrote and edited the manuscript. TK planned and guided the research, and wrote the paper. All authors approved the final version.

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Correspondence to Takaaki Konuma.

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Jimbo, K., Nakajima-Takagi, Y., Ito, T. et al. Immunoglobulin superfamily member 8 maintains myeloid leukemia stem cells through inhibition of β-catenin degradation. Leukemia 36, 1550–1562 (2022). https://doi.org/10.1038/s41375-022-01564-7

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