Skip to main content

Advertisement

SpringerLink
Log in

Differentiation of acute and chronic myeloid leukemic blasts into the dendritic cell lineage: analysis of various differentiation-inducing signals

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose: Ex vivo differentiation of myeloid leukemic blasts into dendritic cells (DCs) holds significant promise for use as cellular vaccines, as they may present a constellation of endogenously expressed known and unknown leukemia antigens to the immune system. Although variety of stimuli can drive leukemia→DC differentiation in vitro, these blast-derived DCs typically have aberrant characteristics compared with DCs generated from normal progenitors by the same stimuli. It is not clear whether this is due to underlying leukemogenic mechanisms (e.g., specific oncogenes), genetic defects, stage of maturation arrest, defects in cytokine receptor expression or signal transduction pathways, or whether different stimuli themselves induce qualitatively dissimilar DC differentiation. Methods: To assess what factors may contribute to aberrant leukemic blast→DC differentiation, we have examined how the same leukemic blasts (AML and CML) respond to different DC differentiation signals—including extracellular (the cytokine combination GM-CSF+TNF-α+IL-4) and intracellular (the protein kinase C agonist PMA, the calcium ionophore A23187, and the combination of PMA plus A23187) stimuli. Results: We have found that the same leukemic blasts will develop qualitatively different sets of DC characteristics in response to differing stimuli, although no stimuli consistently induced all of the characteristic DC features. There were no clear differences in the responses relative to specific oncogene expression or stage of maturation arrest (AML vs CML). Signal transduction agonists that bypassed membrane receptors/proximal signaling (in particular, the combination of PMA and A23187) consistently induced the greatest capability to activate T cells. Interestingly, this ability did not clearly correlate with expression of MHC/costimulatory ligands. Conclusions: Our findings suggest that signal transduction may play an important role in the aberrant DC differentiation of leukemic blasts, and demonstrate that direct activation of PKC together with intracellular calcium signaling may be an effective method for generating immunostimulatory leukemia-derived DCs.

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. 1A–C
Fig. 2
Fig. 3A, B
Fig. 4A, B

Similar content being viewed by others

References

  1. Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W, Ljungman P, Ferrant A, Verdonck L, Niederwieser D (1995) Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 86:2041–2050

    CAS  PubMed  Google Scholar 

  2. Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, Engleman EG, Levy R (1999) Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med 2:52–58

    Google Scholar 

  3. Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S, Taquet N, Rolland A, Taquet S, Coquery S, Wittkowski KM, Bhardwaj N, Pineiro L, Steinman R, Fay J (2001) Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res 61:6451–6458

    CAS  PubMed  Google Scholar 

  4. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    CAS  PubMed  Google Scholar 

  5. Hart DN (1997) Dendritic cells: unique leukocyte populations which control the primary immune response. Blood 90:3245–3287

    PubMed  Google Scholar 

  6. Gong J, Chen D, Kashiwaba M, Li Y, Chen L, Takeuchi H, Qu H, Rowse GJ, Gendler SJ, Kufe D (1998) Reversal of tolerance to human MUC1 antigen in MUC1 transgenic mice immunized with fusions of dendritic and carcinoma cells. Proc Natl Acad Sci U S A 95:6279–6283

    Article  CAS  PubMed  Google Scholar 

  7. Timmerman JM, Levy R (1999) Dendritic cell vaccines for cancer immunotherapy. Annu Rev Med 50:507–529

    CAS  PubMed  Google Scholar 

  8. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811

    CAS  PubMed  Google Scholar 

  9. Ochsenbein AF, Sierro S, Odermatt B, Pericin M, Karrer U, Hermans J, Hemmi S, Hengartner H, Zinkernagel RM (2001) Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 411:1058–1064

    CAS  PubMed  Google Scholar 

  10. Gong J, Chen D, Kashiwaba M, Kufe D (1997) Induction of antitumor activity by immunization with fusions of dendritic and carcinoma cells. Nat Med 3:558–561

    CAS  PubMed  Google Scholar 

  11. Gorin NC, Estey E, Jones RJ, Levitsky HI, Borrello I, Slavin S (2000) New developments in the therapy of acute myelocytic leukemia. Hematology (Am Soc Hematol Educ Program) 2000(1):69–89

  12. Caux C, Dezutter-Dambuyant C, Schmitt D, Banchereau J (1992) GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature 360:258–261

    CAS  PubMed  Google Scholar 

  13. Davis TA (1998) Phorbol esters induce differentiation of human CD34+ hemopoietic progenitors to dendritic cells: evidence for protein kinase C-mediated signaling. J Immunol 160:3689–3697

    CAS  PubMed  Google Scholar 

  14. Zhou LJ, Tedder TF (1996) CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells. Proc Natl Acad Sci U S A 93:2588–2592

    CAS  PubMed  Google Scholar 

  15. Oehler L, Majdic O, Pickl WF, Stockl J, Riedl E, Drach J, Rappersberger K, Geissler K, Knapp W (1998) Neutrophil granulocyte-committed cells can be driven to acquire dendritic cell characteristics. J Exp Med 187:1019–1028

    CAS  PubMed  Google Scholar 

  16. St Louis DC, Woodcock JB, Fransozo G, Blair PJ, Carlson LM, Murillo M, Wells MR, Williams AJ, Smoot DS, Kaushal S, Grimes JL, Harlan DM, Chute JP, June CH, Siebenlist U, Lee KP (1999) Evidence for distinct intracellular signaling pathways in CD34+ progenitor to dendritic cell differentiation from a human cell line model. J Immunol 162:3237–3248

    PubMed  Google Scholar 

  17. Choudhury BA, Liang JC, Thomas EK, Flores-Romo L, Xie QS, Agusala K, Sutaria S, Sinha I, Champlin RE, Claxton DF (1999) Dendritic cells derived in vitro from acute myelogenous leukemia cells stimulate autologous, antileukemic T-cell responses. Blood 93:780–786

    CAS  PubMed  Google Scholar 

  18. Choudhury BA, Liang JC, Thomas EK, Flores-Romo L, Xie QS, Agusala K, Sutaria S, Sinha I, Champlin RE, Claxton DF (1999) Dendritic cells derived in vitro from acute myelogenous leukemia cells stimulate autologous, antileukemic T-cell responses. Blood 93:780–786

    CAS  PubMed  Google Scholar 

  19. Cignetti A, Bryant E, Allione B, Vitale A, Foa R, Cheever MA (1999) CD34(+) acute myeloid and lymphoid leukemic blasts can be induced to differentiate into dendritic cells. Blood 94:2048–2055

    CAS  PubMed  Google Scholar 

  20. Engels FH, Koski GK, Bedrosian I, Xu S, Luger S, Nowell PC, Cohen PA, Czerniecki BJ (1999) Calcium signaling induces acquisition of dendritic cell characteristics in chronic myelogenous leukemia myeloid progenitor cells. Proc Natl Acad Sci U S A 96:10332–10337

    CAS  PubMed  Google Scholar 

  21. Charbonnier A, Gaugler B, Sainty D, Lafage-Pochitaloff M, Olive D (1999) Human acute myeloblastic leukemia cells differentiate in vitro into mature dendritic cells and induce the differentiation of cytotoxic T cells against autologous leukemias. Eur J Immunol 29:2567–2578

    Article  CAS  PubMed  Google Scholar 

  22. Harrison BD, Adams JA, Briggs M, Brereton ML, Yin JA (2001) Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia. Blood 97:2764–2771

    CAS  PubMed  Google Scholar 

  23. Panoskaltsis N, Belanger TJ, Liesveld JL, Abboud CN (2002) Optimal cytokine stimulation for the enhanced generation of leukemic dendritic cells in short-term culture. Leukoc Res 26:191–201

    Article  CAS  Google Scholar 

  24. Mohty M, Isnardon D, Blaise D, Mozziconacci MJ, Lafage-Pochitaloff M, Briere F, Gastaut JA, Olive D, Gaugler B (2002) Identification of precursors of leukemic dendritic cells differentiated from patients with acute myeloid leukemia. Leukemia 16:2267–2274

    Article  CAS  PubMed  Google Scholar 

  25. Paquette RL, Hsu N, Said J, Mohammed M, Rao NP, Shih G, Schiller G, Sawyers C, Glaspy JA (2002) Interferon-alpha induces dendritic cell differentiation of CML mononuclear cells in vitro and in vivo. Leukemia 16:1484–1489

    Article  CAS  PubMed  Google Scholar 

  26. Waclavicek M, Berer A, Oehler L, Stockl J, Schloegl E, Majdic O, Knapp W (2001) Calcium ionophore: a single reagent for the differentiation of primary human acute myelogenous leukaemia cells towards dendritic cells. Br J Haematol 114:466–473

    CAS  PubMed  Google Scholar 

  27. Engels FH, Koski GK, Bedrosian I, Xu S, Luger S, Nowell PC, Cohen PA, Czerniecki BJ (1999) Calcium signaling induces acquisition of dendritic cell characteristics in chronic myelogenous leukemia myeloid progenitor cells. Proc Natl Acad Sci U S A 96:10332–10337

    Article  CAS  PubMed  Google Scholar 

  28. Westers TM, Stam AM, Scheper RJ, Regelink JC, Nieuwint AM, Schuurhuis GJ, van de Loosdrecht AA, Ossenkoppele GJ (2003) Rapid generation of antigen-presenting cells from leukaemic blasts in acute myeloid leukaemia. Cancer Immunol Immunother 52:17–27

    Article  CAS  PubMed  Google Scholar 

  29. Lindner I, Kharfan-Dabaja MA, Ayala E, Kolonias D, Carlson LM, Beazer-Barclay Y, Scherf U, Hnatyszyn JH, Lee KP (2003) Induced dendritic cell differentiation of chronic myeloid leukemia blasts is associated with down-regulation of BCR-ABL. J Immunol 171:1780

    CAS  PubMed  Google Scholar 

  30. Ramadan G, Schmidt RE, Schubert J (2001) In vitro generation of human CD86+ dendritic cells from CD34+ haematopoietic progenitors by PMA and in serum-free medium. Clin Exp Immunol 125:237–244

    Article  CAS  PubMed  Google Scholar 

  31. Fujii S, Shimizu K, Koji F, Kawano F (2003) Malignant counterpart of myeloid dendritic cell (DC) belonging to acute myelogenous leukemia (AML) exhibits a dichotomous immunoregulatory potential. J Leukoc Biol 73:82–90

    Article  CAS  PubMed  Google Scholar 

  32. Eisendle K, Lang A, Eibl B, Nachbaur D, Glassl H, Fiegl M, Thaler J, Gastl G (2003) Phenotypic and functional deficiencies of leukaemic dendritic cells from patients with chronic myeloid leukaemia. Br J Haematol 120:63–73

    Article  PubMed  Google Scholar 

  33. Narita M, Takahashi M, Liu A, Nikkuni K, Furukawa T, Toba K, Koyama S, Takai K, Sanada M, Aizawa Y (2001) Leukemia blast-induced T-cell anergy demonstrated by leukemia-derived dendritic cells in acute myelogenous leukemia. Exp Hematol 29:709–719

    Article  CAS  PubMed  Google Scholar 

  34. Mohty M, Jarrossay D, Lafage-Pochitaloff M, Zandotti C, Briere F, de Lamballeri XN, Isnardon D, Sainty D, Olive D, Gaugler B (2001) Circulating blood dendritic cells from myeloid leukemia patients display quantitative and cytogenetic abnormalities as well as functional impairment. Blood 98:3750–3756

    Article  CAS  PubMed  Google Scholar 

  35. Koski GK, Schwartz GN, Weng DE, Gress RE, Engels FH, Tsokos M, Czerniecki BJ, Cohen PA (1999) Calcium ionophore-treated myeloid cells acquire many dendritic cell characteristics independent of prior differentiation state, transformation status, or sensitivity to biologic agents. Blood 94:1359–1371

    CAS  PubMed  Google Scholar 

  36. Schlienger K, Craighead N, Lee KP, Levine BL, June CH (2000) Efficient priming of protein antigen-specific human CD4(+) T cells by monocyte-derived dendritic cells. Blood 96:3490–3498

    CAS  PubMed  Google Scholar 

  37. June CH, Ledbetter JA, Gillespie MM, Lindsten T, Thompson CB (1987) T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol 7:4472–4481

    CAS  PubMed  Google Scholar 

  38. Yanagawa Y, Onoe K (2002) CCL19 induces rapid dendritic extension of murine dendritic cells. Blood 100:1948–1956

    Article  CAS  PubMed  Google Scholar 

  39. Swetman CA, Leverrier Y, Garg R, Gan CH, Ridley AJ, Katz DR, Chain BM (2002) Extension, retraction and contraction in the formation of a dendritic cell dendrite: distinct roles for Rho GTPases. Eur J Immunol 32:2074–2283

    Article  CAS  PubMed  Google Scholar 

  40. Kobayashi M, Azuma E, Ido M, Hirayama M, Jiang Q, Iwamoto S, Kumamoto T, Yamamoto H, Sakurai M, Komada Y (2001) A pivotal role of Rho GTPase in the regulation of morphology and function of dendritic cells. J Immunol 167:3585–3391

    CAS  PubMed  Google Scholar 

  41. St.Louis DC, Woodcock JB, Fransozo G, Blair PJ, Carlson LM, Murillo M, Wells MR, Williams AJ, Smoot DS, Kaushal S, Grimes JL, Harlan DM, Chute JP, June CH, Siebenlist U, Lee KP (1999) Evidence for distinct intracellular signaling pathways in CD34+ progenitor to dendritic cell differentiation from a human cell line model. J Immunol 162:3237–3248

    PubMed  Google Scholar 

  42. Ryncarz RE, Anasetti C (1998) Expression of CD86 on human marrow CD34(+) cells identifies immunocompetent committed precursors of macrophages and dendritic cells. Blood 91:3892–3900

    CAS  PubMed  Google Scholar 

  43. Alitalo R (1987) The bcr-c-abl tyrosine kinase activity is extinguished by TPA in K562 leukemia cells. FEBS Lett 222:293–298

    Article  CAS  PubMed  Google Scholar 

  44. Campbell ML, Lu D, Guo JQ, Arlinghaus RB (1993) Inhibition of phosphorylation of p160 BCR within p210 BCR-ABL complexes during early stages of phorbol ester-induced differentiation of K562 cells. Cell Growth Differ 4:581–588

    CAS  PubMed  Google Scholar 

  45. Perrin PJ, Davis TA, Smoot DS, Abe R, June CH, Lee KP (1995) Distinct requirements of lymph node T cells for B7-1 (CD80) and B7-2 (CD86) costimulation in response to concanavalin A. Immunology 90:534–542

    Article  Google Scholar 

  46. Liu C, Zhang Y (1991) Phorbol myristate acetate and calcium ionophore A23187 modulate the accessory cell function of mouse dendritic cells. Chin Med Sci J 6:18–23

    CAS  PubMed  Google Scholar 

  47. Davis TA, Saini AA, Blair PJ, Levine BL, Craighead N, Harlan DM, June CH, Lee KP (1998) Phorbol esters induce differentiation of human CD34+ hemopoietic progenitors to dendritic cells: evidence for protein kinase C-mediated signaling. J Immunol 160:3689–3697

    CAS  PubMed  Google Scholar 

  48. Koski GK, Lyakh LA, Cohen PA, Rice NR (2001) CD14+ monocytes as dendritic cell precursors: diverse maturation-inducing pathways lead to common activation of NF-kappab/RelB. Crit Rev Immunol 21:179–189

    CAS  PubMed  Google Scholar 

  49. Sokal JE, Baccarani M, Russo D, Tura S (1988) Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 25:49–61

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, University of Miami, Miami, FL 33136, USA

    Mohamed A. Kharfan-Dabaja, Ernesto Ayala, Nizar J. Bahlis & Kelvin P. Lee

  2. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA

    Mohamed A. Kharfan-Dabaja, Ernesto Ayala, Nizar J. Bahlis & Kelvin P. Lee

  3. Department of Microbiology and Immunology, University of Miami, Miami, FL 33136, USA

    Inna Lindner, Pedro J. Cejas, Despina Kolonias, Louise M. Carlson & Kelvin P. Lee

  4. Department of Microbiology and Immunology, University of Miami School of Medicine, Papanicolaou Bldg., Rm. 211, 1550 NW 10th Ave., Miami, FL 33136, USA

    Kelvin P. Lee

Authors
  1. Mohamed A. Kharfan-Dabaja
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ernesto Ayala
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Inna Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pedro J. Cejas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nizar J. Bahlis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Despina Kolonias
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Louise M. Carlson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kelvin P. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kelvin P. Lee.

Additional information

This work was supported by NIH CA85208, CA95829, and ASCO Young Investigator Award (M.A.K-D)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kharfan-Dabaja, M.A., Ayala, E., Lindner, I. et al. Differentiation of acute and chronic myeloid leukemic blasts into the dendritic cell lineage: analysis of various differentiation-inducing signals. Cancer Immunol Immunother 54, 25–36 (2005). https://doi.org/10.1007/s00262-004-0562-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-004-0562-4

Keywords

Search

Navigation