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:

Tetraspanin CD82 drives acute myeloid leukemia chemoresistance by modulating protein kinase C alpha and β1 integrin activation

Oncogene volume 39, pages 3910–3925 (2020)Cite this article

Subjects

Abstract

A principal challenge in treating acute myeloid leukemia (AML) is chemotherapy refractory disease. As such, there remains a critical need to identify key regulators of chemotherapy resistance in AML. In this study, we demonstrate that the membrane scaffold, CD82, contributes to the chemoresistant phenotype of AML. Using an RNA-seq approach, we identified the increased expression of the tetraspanin family member, CD82, in response to the chemotherapeutic, daunorubicin. Analysis of the TARGET and BEAT AML databases identifies a correlation between CD82 expression and overall survival of AML patients. Moreover, using a combination of cell lines and patient samples, we find that CD82 overexpression results in significantly reduced cell death in response to chemotherapy. Investigation of the mechanism by which CD82 promotes AML survival in response to chemotherapy identified a crucial role for enhanced protein kinase c alpha (PKCα) signaling and downstream activation of the β1 integrin. In addition, analysis of β1 integrin clustering by super-resolution imaging demonstrates that CD82 expression promotes the formation of dense β1 integrin membrane clusters. Lastly, evaluation of survival signaling following daunorubicin treatment identified robust activation of p38 mitogen-activated protein kinase (MAPK) downstream of PKCα and β1 integrin signaling when CD82 is overexpressed. Together, these data propose a mechanism where CD82 promotes chemoresistance by increasing PKCα activation and downstream activation/clustering of β1 integrin, leading to AML cell survival via activation of p38 MAPK. These observations suggest that the CD82-PKCα signaling axis may be a potential therapeutic target for attenuating chemoresistance signaling in AML.

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: Chemotherapy increases the expression of tetraspanin CD82 in AML.
Fig. 2: Increased CD82 expression in AML patient samples correlates with reduced overall survival.
Fig. 3: CD82 overexpression promotes AML chemoresistance.
Fig. 4: PKCα is required for CD82-mediated chemoresistance.
Fig. 5: Chemotherapy activates β1 integrin downstream of PKCα.
Fig. 6: CD82 expression alters β1 integrin membrane clustering.
Fig. 7: Chemotherapy activates p38 MAPK downstream of PKCα and β1 integrin signaling.

Similar content being viewed by others

References

  1. American Cancer Society. Cancer facts & figures. Atlanta, GA: American Cancer Society.

  2. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  CAS  PubMed  Google Scholar 

  3. Nasir SS, Giri S, Nunnery S, Martin MG. Outcome of adolescents and young adults compared with pediatric patients with acute myeloid and promyelocytic leukemia. Clin Lymphoma Myeloma Leuk. 2017;17:126–32. e1.

    Article  PubMed  Google Scholar 

  4. Veuger M, Honders W, Spoelder N, Willemze R, Barge R. Effects of the use of multiple cytotoxic drugs on resistance mechanisms in acute myeloid leukemia. Leukemia. 2001;15:503.

    Article  Google Scholar 

  5. Zhang J, Gu Y, Chen BA. Mechanisms of drug resistance in acute myeloid leukemia. Oncotargets Ther. 2019;12:1937–45.

    Article  Google Scholar 

  6. Cloos J, Goemans BF, Hess CJ, van Oostveen JW, Waisfisz Q, Corthals S, et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia. 2006;20:1217–20.

    Article  CAS  PubMed  Google Scholar 

  7. El Fakih R, Rasheed W, Hawsawi Y, Alsermani M, Hassanein M. Targeting FLT3 mutations in acute myeloid leukemia. Cells. 2018;7:E4.

    Article  PubMed  CAS  Google Scholar 

  8. Cook AM, Li L, Ho YW, Lin A, Li L, Stein A, et al. Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells. Blood. 2014;123:2826–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Basecke J, et al. Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia. 2008;22:708–22.

    Article  CAS  PubMed  Google Scholar 

  10. Bosman MC, Schuringa JJ, Vellenga E. Constitutive NF-kappaB activation in AML: causes and treatment strategies. Crit Rev Oncol Hematol. 2016;98:35–44.

    Article  PubMed  Google Scholar 

  11. Davoudi Z, Akbarzadeh A, Rahmatiyamchi M, Movassaghpour AA, Alipour M, Nejati-Koshki K, et al. Molecular target therapy of AKT and NF-kB signaling pathways and multidrug resistance by specific cell penetrating inhibitor peptides in HL-60 cells. Asian Pac J Cancer Prev. 2014;15:4353–8.

    Article  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. 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  PubMed  PubMed Central  Google Scholar 

  15. Boyer T, Guihard S, Roumier C, Peyrouze P, Gonzales F, Berthon C, et al. Tetraspanin CD81 is an adverse prognostic marker in acute myeloid leukemia. Oncotarget. 2016;7:62377–85.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Burchert A, Notter M, Menssen HD, Schwartz S, Knauf W, Neubauer A, et al. CD82 (KAI1), a member of the tetraspan family, is expressed on early haemopoietic progenitor cells and up-regulated in distinct human leukaemias. Brit J Haematol. 1999;107:494–504.

    Article  CAS  Google Scholar 

  17. Saito-Reis CA, Marjon KD, Pascetti EM, Floren M, Gillette JM. The tetraspanin CD82 regulates bone marrow homing and engraftment of hematopoietic stem and progenitor cells. Mol Biol Cell. 2018;29:2946–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nishioka C, Ikezoe T, Yang J, Yokoyama A. Tetraspanin family member, CD82, regulates expression of EZH2 via inactivation of p38 MAPK signaling in leukemia cells. PLoS ONE. 2015;10:e0125017.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Marjon KD, Termini CM, Karlen KL, Saito-Reis C, Soria CE, Lidke KA, et al. Tetraspanin CD82 regulates bone marrow homing of acute myeloid leukemia by modulating the molecular organization of N-cadherin. Oncogene. 2016;35:4132–40.

    Article  CAS  PubMed  Google Scholar 

  20. Termini CM, Lidke KA, Gillette JM. Tetraspanin CD82 regulates the spatiotemporal dynamics of PKC alpha in acute myeloid leukemia. Sci Rep. 2016;29895.

  21. Kurinna S, Konopleva M, Palla SL, Chen W, Kornblau S, Contractor R, et al. Bcl2 phosphorylation and active PKC alpha are associated with poor survival in AML. Leukemia. 2006;20:1316–9.

    Article  CAS  PubMed  Google Scholar 

  22. Ruvolo PP, Zhou LR, Watt JC, Ruvolo VR, Burks JK, Jiffar T, et al. Targeting pkc-mediated signal transduction pathways using enzastaurin to promote apoptosis in acute myeloid leukemia-derived cell lines and blast cells. J Cell Biochem. 2011;112:1696–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wakui M, Kuriyama K, Miyazaki Y, Hata T, Taniwaki M, Ohtake S, et al. Diagnosis of acute myeloid leukemia according to the WHO classification in the Japan Adult Leukemia Study Group AML-97 protocol. Int J Hematol. 2008;87:144–51.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Walter RB, Othus M, Burnett AK, Lowenberg B, Kantarjian HM, Ossenkoppele GJ, et al. Significance of FAB subclassification of “acute myeloid leukemia, NOS” in the 2008 WHO classification: analysis of 5848 newly diagnosed patients. Blood. 2013;121:2424–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Byun JM, Kim YJ, Yoon HJ, Kim SY, Kim HJ, Yoon J, et al. Cytogenetic profiles of 2806 patients with acute myeloid leukemia-a retrospective multicenter nationwide study. Ann Hematol. 2016;95:1223–32.

    Article  PubMed  Google Scholar 

  26. Okamoto Y, Kudo K, Tabuchi K, Tomizawa D, Taga T, Goto H, et al. Hematopoietic stem-cell transplantation in children with refractory acute myeloid leukemia. Bone Marrow Transpl. 2019;54:1489–98.

    Article  CAS  Google Scholar 

  27. Takami M, Katayama K, Noguchi K, Sugimoto Y. Protein kinase C alpha-mediated phosphorylation of PIM-1L promotes the survival and proliferation of acute myeloid leukemia cells. Biochem Biophys Res Commun. 2018;503:1364–71.

    Article  CAS  PubMed  Google Scholar 

  28. Efimova T, Deucher A, Kuroki T, Ohba M, Eckert RL. Novel protein kinase C isoforms regulate human keratinocyte differentiation by activating a p38 delta mitogen-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha. J Biol Chem. 2002;277:31753–60.

    Article  CAS  PubMed  Google Scholar 

  29. Hocevar BA, Morrow DM, Tykocinski ML, Fields AP. Protein kinase C isotypes in human erythroleukemia cell proliferation and differentiation. J Cell Sci. 1992;101:671–9.

    CAS  PubMed  Google Scholar 

  30. Myklebust JH, Smeland EB, Josefsen D, Sioud M. Protein kinase C-alpha isoform is involved in erythropoietin-induced erythroid differentiation of CD34(+) progenitor cells from human bone marrow. Blood. 2000;95:510–8.

    Article  CAS  PubMed  Google Scholar 

  31. Jin JK, Tien PC, Cheng CJ, Song JH, Huang C, Lin SH, et al. Talin1 phosphorylation activates beta1 integrins: a novel mechanism to promote prostate cancer bone metastasis. Oncogene. 2015;34:1811–21.

    Article  CAS  PubMed  Google Scholar 

  32. Ramirez P, Rettig MP, Uy GL, Deych E, Holt MS, Ritchey JK, et al. BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells. Blood. 2009;114:1340–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. van Kooyk Y, Figdor CG. Avidity regulation of integrins: the driving force in leukocyte adhesion. Curr Opin Cell Biol. 2000;12:542–7.

    Article  PubMed  Google Scholar 

  34. Kolanus W, Seed B. Integrins and inside-out signal transduction: converging signals from PKC and PIP3. Curr Opin Cell Biol. 1997;9:725–31.

    Article  CAS  PubMed  Google Scholar 

  35. Martin Ester H-PK, Jorg Sander, Xiaowei Xu. A density-based algorithm for discovering clusters in large spatial databases with noise. In Proceedings of the 2nd International Conference on Knowledge Discovery and Data Mining (KDD-96). Portland, Oregon: AAAI Press; 1996. p. 226–31.

  36. Thornton TM, Rincon M. Non-classical p38 map kinase functions: cell cycle checkpoints and survival. Int J Biol Sci. 2009;5:44–51.

    Article  CAS  PubMed  Google Scholar 

  37. Wood CD, Thornton TM, Sabio G, Davis RA, Rincon M. Nuclear localization of p38 MAPK in response to DNA damage. Int J Biol Sci. 2009;5:428–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gupta J, Igea A, Papaioannou M, Lopez-Casas PP, Llonch E, Hidalgo M, et al. Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors. Oncotarget. 2015;6:8539–51.

    PubMed  PubMed Central  Google Scholar 

  39. Naci D, Aoudjit F. Alpha2beta1 integrin promotes T cell survival and migration through the concomitant activation of ERK/Mcl-1 and p38 MAPK pathways. Cell Signal. 2014;26:2008–15.

    Article  CAS  PubMed  Google Scholar 

  40. Scott MJ, Billiar TR. Beta2-integrin-induced p38 MAPK activation is a key mediator in the CD14/TLR4/MD2-dependent uptake of lipopolysaccharide by hepatocytes. J Biol Chem. 2008;283:29433–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hwang S, Takimoto T, Hemler ME. Integrin-independent support of cancer drug resistance by tetraspanin CD151. Cell Mol Life Sci. 2019;76:1595–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ye M, Wei T, Wang Q, Sun Y, Tang R, Guo L, et al. TSPAN12 promotes chemoresistance and proliferation of SCLC under the regulation of miR-495. Biochem Biophys Res Commun. 2017;486:349–56.

    Article  CAS  PubMed  Google Scholar 

  43. 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 

  44. Ullah M, Akbar A, Ng NN, Concepcion W, Thakor AS. Mesenchymal stem cells confer chemoresistance in breast cancer via a CD9 dependent mechanism. Oncotarget. 2019;10:3435–50.

    PubMed  PubMed Central  Google Scholar 

  45. Nishioka C, Ikezoe T, Yang J, Nobumoto A, Kataoka S, Tsuda M, et al. CD82 regulates STAT5/IL-10 and supports survival of acute myelogenous leukemia cells. Int J Cancer. 2014;134:55–64.

    Article  PubMed  CAS  Google Scholar 

  46. Ji H, Chen L, Xing Y, Li S, Dai J, Zhao P, et al. CD82 supports survival of childhood acute myeloid leukemia cells via activation of Wnt/beta-catenin signaling pathway. Pediatr Res. 2019;85:1024–31.

    Article  PubMed  CAS  Google Scholar 

  47. Nishioka C, Ikezoe T, Takeuchi A, Nobumoto A, Tsuda M, Yokoyama A. The novel function of CD82 and its impact on BCL2L12 via AKT/STAT5 signal pathway in acute myelogenous leukemia cells. Leukemia. 2015;29:2296–306.

    Article  CAS  PubMed  Google Scholar 

  48. Bonardi F, Fusetti F, Deelen P, van Gosliga D, Vellenga E, Schuringa JJ. A proteomics and transcriptomics approach to identify leukemic stem cell (LSC) markers. Mol Cell Proteom. 2013;12:626–37.

    Article  CAS  Google Scholar 

  49. Tonoli H, Barrett JC. CD82 metastasis suppressor gene: a potential target for new therapeutics? Trends Mol Med. 2005;11:563–70.

    Article  CAS  PubMed  Google Scholar 

  50. Miranti CK. Controlling cell surface dynamics and signaling: how CD82/KAI1 suppresses metastasis. Cell Signal 2009;21:196–211.

    Article  CAS  PubMed  Google Scholar 

  51. Tsai YC, Weissman AM. Dissecting the diverse functions of the metastasis suppressor CD82/KAI1. FEBS Lett. 2011;585:3166–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Nishioka C, Ikezoe T, Furihata M, Yang J, Serada S, Naka T, et al. CD34+/CD38 acute myelogenous leukemia cells aberrantly express CD82 which regulates adhesion and survival of leukemia stem cells. Int J Cancer. 2013;132:2006–19.

    Article  CAS  PubMed  Google Scholar 

  53. Brockstein B, Samuels B, Humerickhouse R, Arietta R, Fishkin P, Wade J. et al. Phase II studies of bryostatin-1 in patients with advanced sarcoma and advanced head and neck cancer. Invest New Drugs. 2001;19:249–54.

    Article  CAS  PubMed  Google Scholar 

  54. Varterasian ML, Mohammad RM, Shurafa MS, Hulburd K, Pemberton PA, Rodriguez DH, et al. Phase II trial of bryostatin 1 in patients with relapsed low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Clin Cancer Res. 2000;6:825–8.

    CAS  PubMed  Google Scholar 

  55. Crump M, Leppa S, Fayad L, Lee JJ, Di Rocco A, Ogura M, et al. Randomized, double-blind, phase III trial of enzastaurin versus placebo in patients achieving remission after first-line therapy for high-risk diffuse large b-cell lymphoma. J Clin Oncol. 2016;34:2484–92.

    Article  CAS  PubMed  Google Scholar 

  56. Aoudjit F, Vuori K. Integrin signaling in cancer cell survival and chemoresistance. Chemother Res Pract. 2012;2012:283181.

    PubMed  PubMed Central  Google Scholar 

  57. Naci D, El Azreq MA, Chetoui N, Lauden L, Sigaux F, Charron D, et al. alpha2beta1 integrin promotes chemoresistance against doxorubicin in cancer cells through extracellular signal-regulated kinase (ERK). J Biol Chem. 2012;287:17065–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nair MG, Desai K, Prabhu JS, Hari PS, Remacle J, Sridhar TS. beta3 integrin promotes chemoresistance to epirubicin in MDA-MB-231 through repression of the pro-apoptotic protein, BAD. Exp Cell Res. 2016;346:137–45.

    Article  CAS  PubMed  Google Scholar 

  59. Sansing HA, Sarkeshik A, Yates JR, Patel V, Gutkind JS, Yamada KM, et al. Integrin alphabeta1, alphavbeta, alpha6beta effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance. Biochem Biophys Res Commun. 2011;406:171–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Seguin L, Desgrosellier JS, Weis SM, Cheresh DA. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 2015;25:234–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Berrazouane S, Boisvert M, Salti S, Mourad W, Al-Daccak R, Barabe F, et al. Beta1 integrin blockade overcomes doxorubicin resistance in human T-cell acute lymphoblastic leukemia. Cell Death Dis. 2019;10:357.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Zhang XA, Bontrager AL, Hemler ME. Transmembrane-4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific beta(1) integrins. J Biol Chem. 2001;276:25005–13.

    Article  CAS  PubMed  Google Scholar 

  63. Termini CM, Cotter ML, Marjon KD, Buranda T, Lidke K, Gillette JM. Regulation of VLA-4 mediated hematopoietic stem/progenitor cell adhesion by CD82. Mol Biol Cell. 2012;23:1545–1697.

    Google Scholar 

  64. Bachegowda L, Morrone K, Winski SL, Mantzaris I, Bartenstein M, Ramachandra N, et al. Pexmetinib: a novel dual inhibitor of Tie2 and p38 MAPK with efficacy in preclinical models of myelodysplastic syndromes and acute myeloid leukemia. Cancer Res. 2016;76:4841–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Garcia-Manero G, Khoury HJ, Jabbour E, Lancet J, Winski SL, Cable L, et al. A phase I study of oral ARRY-614, a p38 MAPK/Tie2 dual inhibitor, in patients with low or intermediate-1 risk myelodysplastic syndromes. Clin Cancer Res. 2015;21:985–94.

    Article  CAS  PubMed  Google Scholar 

  66. Beckwith KA, Byrd JC, Muthusamy N. Tetraspanins as therapeutic targets in hematological malignancy: a concise review. Front Physiol. 2015;6:91.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Brown RB, Madrid NJ, Suzuki H, Ness SA. Optimized approach for Ion Proton RNA sequencing reveals details of RNA splicing and editing features of the transcriptome. PLoS ONE. 2017;12:e0176675.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Brayer KJ, Frerich CA, Kang H, Ness SA. Recurrent fusions in MYB and MYBL1 define a common, transcription factor-driven oncogenic pathway in salivary gland adenoid cystic carcinoma. Cancer Discov. 2016;6:176–87.

    Article  CAS  PubMed  Google Scholar 

  69. Frerich CA, Brayer KJ, Painter BM, Kang H, Mitani Y, El-Naggar AK, et al. Transcriptomes define distinct subgroups of salivary gland adenoid cystic carcinoma with different driver mutations and outcomes. Oncotarget. 2018;9:7341–58.

    Article  PubMed  Google Scholar 

  70. Anders S, Pyl PT, Huber W. HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.

    Article  CAS  PubMed  Google Scholar 

  71. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    Article  CAS  PubMed  Google Scholar 

  72. Varet H, Brillet-Gueguen L, Coppee JY, Dillies MA. SARTools: a DESeq2- and EdgeR-based R pipeline for comprehensive differential analysis of RNA-Seq data. PLoS ONE. 2016;11:e0157022.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Saldanha AJ. Java treeview-extensible visualization of microarray data. Bioinformatics. 2004;20:3246–8.

    Article  CAS  PubMed  Google Scholar 

  74. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Druker BJ, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562:526–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Valley CC, Liu S, Lidke DS, Lidke KA. Sequential superresolution imaging of multiple targets using a single fluorophore. PLoS ONE. 2015;10:e0123941.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Huang F, Schwartz SL, Byars JM, Lidke KA. Simultaneous multiple-emitter fitting for single molecule super-resolution imaging. Biomed Opt Express. 2011;2:1377–93.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by fellowships: F31CA232480 to MF, F31HL124977 to CMT, and T32HL007736 to KDM, and an NHLBI investigator grant (RO1HL122483 to JMG), and an American Cancer Society Research Scholar Grant (130675 to JMG). This work was partially supported by the UNM Spatiotemporal Modeling Center (P50GM085273) and the UNM Comprehensive Cancer Center Support Grant (P30CA118100) through the following shared resources: Analytical and Translational Genomics, Human Tissue Repository, Fluorescence Microscopy, Flow Cytometry and Biostatistics. We also acknowledge Victoria Balise for critical manuscript review and the experimental assistance of Christian Doyle.

Author information

Authors and Affiliations

  1. Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

    Muskan Floren, Sebastian Restrepo Cruz, Christina M. Termini, Kristopher D. Marjon & Jennifer M. Gillette

  2. Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM, USA

    Keith A. Lidke

  3. University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, 87131, USA

    Keith A. Lidke & Jennifer M. Gillette

Authors
  1. Muskan Floren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sebastian Restrepo Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christina M. Termini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kristopher D. Marjon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keith A. Lidke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jennifer M. Gillette
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer M. Gillette.

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

Floren, M., Restrepo Cruz, S., Termini, C.M. et al. Tetraspanin CD82 drives acute myeloid leukemia chemoresistance by modulating protein kinase C alpha and β1 integrin activation. Oncogene 39, 3910–3925 (2020). https://doi.org/10.1038/s41388-020-1261-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-020-1261-0

This article is cited by

Search

Advanced search

Quick links