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.

  • Article
  • Published:

Acute lymphoblastic leukemia

CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity

Leukemia volume 34, pages 709–720 (2020)Cite this article

Subjects

Abstract

CD9 has been implicated in cancer progression but its prognostic relevance and therapeutic potential in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are largely unknown. In a cohort of pediatric BCP-ALL patients, we found that CD9+ cases had a significantly lower 5-year relapse-free survival rate than CD9− cases. Multivariate analysis demonstrated that CD9 positivity independently predicted inferior survival outcomes, and could be applied with established prognostic features, including prednisone response and cytogenetic status, to refine patient stratification. Administration of CD9 antibody substantially suppressed disease progression in NOD/SCID mice xenografted with CD9+ cell lines and primary leukemic blasts from patients with high-risk and refractory BCP-ALL, without compromising hematopoietic stem cell engraftment. Combination of anti-CD9 with conventional chemotherapy further reduced leukemic burden and prolonged animal survival. Mechanistically, CD9 blockade inhibited leukemic cell proliferation, induced G0/G1 cell cycle arrest, activated p38, and enhanced chemotherapeutic agent-induced apoptosis. Further, CD9 physically interacted with integrin very late antigen-4, regulated affinity to vascular cell adhesion molecule-1, and was involved in leukemia–stroma interaction. Collectively, our study established CD9 as a new prognostic marker, validated the preclinical efficacy of CD9 antibody, and laid the foundation for clinical development of CD9-targeted therapy for high-risk and refractory pediatric BCP-ALL.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120:1165–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Harrison CJ. Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia. Br J Haematol. 2009;144:147–56.

    Article  PubMed  Google Scholar 

  3. Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373:1541–52.

    Article  CAS  PubMed  Google Scholar 

  4. Mullighan CG. Molecular genetics of B-precursor acute lymphoblastic leukemia. J Clin Invest. 2012;122:3407–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bhojwani D, Pui CH. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 2013;14:e205–17.

    Article  PubMed  Google Scholar 

  6. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Clay D, Rubinstein E, Mishal Z, Anjo A, Prenant M, Jasmin C, et al. CD9 and megakaryocyte differentiation. Blood. 2001;97:1982–9.

    Article  CAS  PubMed  Google Scholar 

  11. Qi JC, Wang J, Mandadi S, Tanaka K, Roufogalis BD, Madigan MC, et al. Human and mouse mast cells use the tetraspanin CD9 as an alternate interleukin-16 receptor. Blood. 2006;107:135–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Masellis-Smith A, Shaw AR. CD9-regulated adhesion. Anti-CD9 monoclonal antibody induce pre-B cell adhesion to bone marrow fibroblasts through de novo recognition of fibronectin. J Immunol. 1994;152:2768–77.

    CAS  PubMed  Google Scholar 

  13. 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  CAS  PubMed  Google Scholar 

  14. Leung KT, Chan KY, Ng PC, Lau TK, Chiu WM, Tsang KS, et al. The tetraspanin CD9 regulates migration, adhesion, and homing of human cord blood CD34+ hematopoietic stem and progenitor cells. Blood. 2011;117:1840–50.

    Article  CAS  PubMed  Google Scholar 

  15. Kischel P, Bellahcene A, Deux B, Lamour V, Dobson R, DE Pauw E, et al. Overexpression of CD9 in human breast cancer cells promotes the development of bone metastases. Anticancer Res. 2012;32:5211–20.

    CAS  PubMed  Google Scholar 

  16. Hori H, Yano S, Koufuji K, Takeda J, Shirouzu K. CD9 expression in gastric cancer and its significance. J Surg Res. 2004;117:208–15.

    Article  CAS  PubMed  Google Scholar 

  17. Kohmo S, Kijima T, Otani Y, Mori M, Minami T, Takahashi R, et al. Cell surface tetraspanin CD9 mediates chemoresistance in small cell lung cancer. Cancer Res. 2010;70:8025–35.

    Article  CAS  PubMed  Google Scholar 

  18. Sauer G, Windisch J, Kurzeder C, Heilmann V, Kreienberg R, Deissler H. Progression of cervical carcinomas is associated with down-regulation of CD9 but strong local re-expression at sites of transendothelial invasion. Clin Cancer Res. 2003;9:6426–31.

    CAS  PubMed  Google Scholar 

  19. Wang JC, Bégin LR, Bérubé NG, Chevalier S, Aprikian AG, Gourdeau H, et al. Down-regulation of CD9 expression during prostate carcinoma progression is associated with CD9 mRNA modifications. Clin Cancer Res. 2007;13:2354–61.

    Article  CAS  PubMed  Google Scholar 

  20. Tang M, Yin G, Wang F, Liu H, Zhou S, Ni J, et al. Downregulation of CD9 promotes pancreatic cancer growth and metastasis through upregulation of epidermal growth factor on the cell surface. Oncol Rep. 2015;34:350–8.

    Article  CAS  PubMed  Google Scholar 

  21. De Bruyne E, Bos TJ, Asosingh K, Vande Broek I, Menu E, Van Valckenborgh E, et al. Epigenetic silencing of the tetraspanin CD9 during disease progression in multiple myeloma cells and correlation with survival. Clin Cancer Res. 2008;14:2918–26.

    Article  PubMed  Google Scholar 

  22. Zöller M. Tetraspanins: push and pull in suppressing and promoting metastasis. Nat Rev Cancer. 2009;9:40–55.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Herr MJ, Kotha J, Hagedorn N, Smith B, Jennings LK. Tetraspanin CD9 promotes the invasive phenotype of human fibrosarcoma cells via upregulation of matrix metalloproteinase-9. PLoS One. 2013;8:e67766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gandemer V, Rio AG, de Tayrac M, Sibut V, Mottier S, Ly Sunnaram B, et al. Five distinct biological processes and 14 differentially expressed genes characterize TEL/AML1-positive leukemia. BMC Genomics. 2007;8:385.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gandemer V, Aubry M, Roussel M, Rio AG, de Tayrac M, Vallee A, et al. CD9 expression can be used to predict childhood TEL/AML1-positive acute lymphoblastic leukemia: proposal for an accelerated diagnostic flowchart. Leuk Res. 2010;34:430–7.

    Article  CAS  PubMed  Google Scholar 

  28. Nishida H, Yamazaki H, Yamada T, Iwata S, Dang NH, Inukai T, et al. CD9 correlates with cancer stem cell potentials in human B-acute lymphoblastic leukemia cells. Biochem Biophys Res Commun. 2009;382:57–62.

    Article  CAS  PubMed  Google Scholar 

  29. Aoki Y, Watanabe T, Saito Y, Kuroki Y, Hijikata A, Takagi M, et al. Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia. Blood. 2015;125:967–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yamazaki H, Xu CW, Naito M, Nishida H, Okamoto T, Ghani FI, et al. Regulation of cancer stem cell properties by CD9 in human B-acute lymphoblastic leukemia. Biochem Biophys Res Commun. 2011;409:14–21.

    Article  CAS  PubMed  Google Scholar 

  31. Arnaud MP, Vallée A, Robert G, Bonneau J, Leroy C, Varin-Blank N, et al. CD9, a key actor in the dissemination of lymphoblastic leukemia, modulating CXCR4-mediated migration via RAC1 signaling. Blood. 2015;126:1802–12.

    Article  CAS  PubMed  Google Scholar 

  32. Li CK, Chik KW, Ha SY, Lee AC, Yuen HL, Ling SC, et al. Improved outcome of acute lymphoblastic leukaemia treated by delayed intensification in Hong Kong children: HKALL97 study. Hong Kong Med J. 2006;12:33–9.

    CAS  PubMed  Google Scholar 

  33. Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S, et al. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014;32:174–84.

    Article  CAS  PubMed  Google Scholar 

  34. Cui L, Li ZG, Chai YH, Yu J, Gao J, Zhu XF, et al. Outcome of children with newly diagnosed acute lymphoblastic leukemia treated with CCLG-ALL 2008: the first nation-wide prospective multicenter study in China. Am J Hematol. 2018;93:913–20.

    Article  PubMed  Google Scholar 

  35. Kang MH, Kang YH, Szymanska B, Wilczynska-Kalak U, Sheard MA, Harned TM, et al. Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. Blood. 2007;110:2057–66.

    Article  CAS  PubMed  Google Scholar 

  36. Li K, Chuen CK, Lee SM, Law P, Fok TF, Ng PC, et al. Small peptide analogue of SDF-1alpha supports survival of cord blood CD34+ cells in synergy with other cytokines and enhances their ex vivo expansion and engraftment into nonobese diabetic/severe combined immunodeficient mice. Stem Cells. 2006;24:55–64.

    Article  CAS  PubMed  Google Scholar 

  37. Chan JR, Hyduk SJ, Cybulsky MI. Chemoattractants induce a rapid and transient upregulation of monocyte alpha4 integrin affinity for vascular cell adhesion molecule 1 which mediates arrest: an early step in the process of emigration. J Exp Med. 2001;193:1149–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhi Q, Wang Y, Wang X, Yue D, Li K, Jiang R. Predictive and prognostic value of preoperative serum tumor markers in resectable adenosqamous lung carcinoma. Oncotarget. 2016;7:64798–809.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Walter RB, Alonzo TA, Gerbing RB, Ho PA, Smith FO, Raimondi SC, et al. High expression of the very late antigen-4 integrin independently predicts reduced risk of relapse and improved outcome in pediatric acute myeloid leukemia: a report from the children’s oncology group. J Clin Oncol. 2010;28:2831–8.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, et al. Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics. 2016;32:2866–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liang P, Miao M, Liu Z, Wang H, Jiang W, Ma S, et al. CD9 expression indicates a poor outcome in acute lymphoblastic leukemia. Cancer Biomark. 2018;21:781–6.

    Article  CAS  PubMed  Google Scholar 

  42. Nakamoto T, Murayama Y, Oritani K, Boucheix C, Rubinstein E, Nishida M, et al. A novel therapeutic strategy with anti-CD9 antibody in gastric cancers. J Gastroenterol. 2009;44:889–96.

    Article  CAS  PubMed  Google Scholar 

  43. Ovalle S, Gutiérrez-López MD, Olmo N, Turnay J, Lizarbe MA, Majano P, et al. The tetraspanin CD9 inhibits the proliferation and tumorigenicity of human colon carcinoma cells. Int J Cancer. 2007;121:2140–52.

    Article  CAS  PubMed  Google Scholar 

  44. Gaudichon J, Jakobczyk H, Debaize L, Cousin E, Galibert MD, Troadec MB, et al. Mechanisms of extramedullary relapse in acute lymphoblastic leukemia: reconciling biological concepts and clinical issues. Blood Rev. 2019; https://doi.org/10.1016/j.blre.2019.04.003.

  45. Aldoss I, Song J, Stiller T, Nguyen T, Palmer J, O’Donnell M, et al. Correlates of resistance and relapse during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. Am J Hematol. 2017;92:858–65.

    Article  CAS  PubMed  Google Scholar 

  46. Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016;127:2406–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Frismantas V, Dobay MP, Rinaldi A, Tchinda J, Dunn SH, Kunz J, et al. Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. Blood. 2017;129:e26–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Carloni V, Mazzocca A, Mello T, Galli A, Capaccioli S. Cell fusion promotes chemoresistance in metastatic colon carcinoma. Oncogene. 2013;32:2649–60.

    Article  CAS  PubMed  Google Scholar 

  49. Jang JK, Khawli LA, Park R, Wu BW, Li Z, Canter D, et al. Cytoreductive chemotherapy improves the biodistribution of antibodies directed against tumor necrosis in murine solid tumor models. Mol Cancer Ther. 2013;12:2827–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rendu F, Boucheix C, Lebret M, Bourdeau N, Benoit P, Maclouf J, et al. Mechanisms of the mAb ALB6(CD9) induced human platelet activation: comparison with thrombin. Biochem Biophys Res Commun. 1987;146:1397–404.

    Article  CAS  PubMed  Google Scholar 

  51. Jennings LK, Fox CF, Kouns WC, McKay CP, Ballou LR, Schultz HE. The activation of human platelets mediated by anti-human platelet p24/CD9 monoclonal antibodies. J Biol Chem. 1990;265:3815–22.

    CAS  PubMed  Google Scholar 

  52. Kawakatsu T, Suzuki M, Kido H, Sakane H, Hada S, Yamaguchi K, et al. Antithrombotic effect of an anti-glycoprotein IIB/IIIA antibody in primate lethal thrombosis. Thromb Res. 1993;70:245–54.

    Article  CAS  PubMed  Google Scholar 

  53. Taylor SM, Reilly MP, Schreiber AD, Chien P, Tuckosh JR, McKenzie SE. Thrombosis and shock induced by activating antiplatelet antibodies in human Fc gamma RIIA transgenic mice: the interplay among antibody, spleen, and Fc receptor. Blood. 2000;96:4254–60.

    Article  CAS  PubMed  Google Scholar 

  54. Tomiyama Y, Kunicki TJ, Zipf TF, Ford SB, Aster RH. Response of human platelets to activating monoclonal antibodies: importance of Fc gamma RII (CD32) phenotype and level of expression. Blood. 1992;80:2261–8.

    Article  CAS  PubMed  Google Scholar 

  55. Gachet C, Astier A, de la Salle H, de la Salle C, Fridman WH, Cazenave JP, et al. Release of Fc gamma RIIa2 by activated platelets and inhibition of anti-CD9-mediated platelet aggregation by recombinant Fc gamma RIIa2. Blood. 1995;85:698–704.

    Article  CAS  PubMed  Google Scholar 

  56. Schewe DM, Alsadeq A, Sattler C, Lenk L, Vogiatzi F, Cario G, et al. An Fc-engineered CD19 antibody eradicates MRD in patient-derived MLL-rearranged acute lymphoblastic leukemia xenografts. Blood. 2017;130:1543–52.

    Article  CAS  PubMed  Google Scholar 

  57. Dijoseph JF, Dougher MM, Armellino DC, Evans DY, Damle NK. Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia. Leukemia. 2007;21:2240–5.

    Article  CAS  PubMed  Google Scholar 

  58. Gutiérrez-López MD, Ovalle S, Yáñez-Mó M, Sánchez-Sánchez N, Rubinstein E, Olmo N, et al. A functionally relevant conformational epitope on the CD9 tetraspanin depends on the association with activated beta1 integrin. J Biol Chem. 2003;278:208–18.

    Article  CAS  PubMed  Google Scholar 

  59. Kotha J, Longhurst C, Appling W, Jennings LK. Tetraspanin CD9 regulates beta 1 integrin activation and enhances cell motility to fibronectin via a PI-3 kinase-dependent pathway. Exp Cell Res. 2008;314:1811–22.

    Article  CAS  PubMed  Google Scholar 

  60. Pellinen T, Rantala JK, Arjonen A, Mpindi JP, Kallioniemi O, Ivaska J. A functional genetic screen reveals new regulators of beta1-integrin activity. J Cell Sci. 2012;125:649–61.

    Article  CAS  PubMed  Google Scholar 

  61. Jacamo R, Chen Y, Wang Z, Ma W, Zhang M, Spaeth EL, et al. Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance. Blood. 2014;123:2691–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hsieh YT, Gang EJ, Geng H, Park E, Huantes S, Chudziak D, et al. Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy. Blood. 2013;121:1814–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Coulthard LR, White DE, Jones DL, McDermott MF, Burchill SA. p38(MAPK): stress responses from molecular mechanisms to therapeutics. Trends Mol Med. 2009;15:369–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Murayama Y, Miyagawa J, Oritani K, Yoshida H, Yamamoto K, Kishida O, et al. CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells. J Cell Sci. 2004;117:3379–88.

    Article  CAS  PubMed  Google Scholar 

  65. Hu Y, Liu Y, Pelletier S, Buchdunger E, Warmuth M, Fabbro D, et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet. 2004;36:453–61.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the Research Grants Council, University Grants Committee, Hong Kong (project no: 14108615) and the Children’s Cancer Foundation, Hong Kong (project no: 7104593); and by a Direct Grant for Research from The Chinese University of Hong Kong, Hong Kong (project no: 4054291). The funding bodies were not involved in the study design, the collection, analysis and interpretation of data, or the decision to submit the paper for publication.

Author information

Author notes

  1. These authors contributed equally: Kam Tong Leung, Chi Zhang, Kathy Yuen Yee Chan

Authors and Affiliations

  1. Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong

    Kam Tong Leung, Chi Zhang, Kathy Yuen Yee Chan, Karen Li, John Tak Kit Cheung, Jasmine Wai Sum Yu, Toni Ki Fong Man, Han Wang, Kam Sze Tsang, Frankie Wai Tsoi Cheng, Grace Kee See Lam, Tin Wai Chow, Alex Wing Kwan Leung, Ting Fan Leung, Patrick Man Pan Yuen, Pak Cheung Ng & Chi Kong Li

  2. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong

    Margaret Heung Ling Ng, Wei Kang & Ka Fai To

  3. Department of Medicine, Loma Linda University, Loma Linda, CA, USA

    Xiao-Bing Zhang

  4. Department of Statistics, The Chinese University of Hong Kong, Shatin, Hong Kong

    Tony Sit

  5. Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, Hong Kong

    Wayne Yuk Wai Lee

Authors
  1. Kam Tong Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathy Yuen Yee Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John Tak Kit Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Margaret Heung Ling Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao-Bing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tony Sit
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wayne Yuk Wai Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wei Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ka Fai To
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jasmine Wai Sum Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Toni Ki Fong Man
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Han Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kam Sze Tsang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Frankie Wai Tsoi Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Grace Kee See Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Tin Wai Chow
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Alex Wing Kwan Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Ting Fan Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Patrick Man Pan Yuen
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Pak Cheung Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Chi Kong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KTL, KL, TFL, PMPY, PCN, and CKL conceived the study, interpreted data and wrote the paper. CZ, JTKC, JWSY, TKFM, and HW collected and analyzed data. KYYC and TS performed statistical analyses. MHLN, KST, FWTC, GKSL, TWC, and AWKL provided patient samples. XBZ, WYWL, WK, and KFT contributed to essential laboratory reagents. All authors reviewed and approved the final paper.

Corresponding authors

Correspondence to Kam Tong Leung or Chi Kong Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leung, K.T., Zhang, C., Chan, K.Y.Y. et al. CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity. Leukemia 34, 709–720 (2020). https://doi.org/10.1038/s41375-019-0593-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-019-0593-7

This article is cited by

Search

Advanced search

Quick links