Experimental Hematology
Volume 38, Issue 3 , Pages 180-190 , March 2010

Impact of CXCR4 inhibition on FLT3-ITD−positive human AML blasts

  • Angela Jacobi

      Affiliations

    • Department of Pediatrics, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
    • Drs. Jacobi and Thieme contributed equally to this work.
    • ,
  • Sebastian Thieme

      Affiliations

    • Department of Pediatrics, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
    • DFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany
    • Drs. Jacobi and Thieme contributed equally to this work.
    • ,
  • Romy Lehmann

      Affiliations

    • Department of Pediatrics, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
    • ,
  • Fernando Ugarte

      Affiliations

    • Department of Pediatrics, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
    • ,
  • Harry L. Malech

      Affiliations

    • Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md., USA
    • ,
  • Sina Koch

      Affiliations

    • Medical Clinic I, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
    • ,
  • Christian Thiede

      Affiliations

    • DFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany
    • Medical Clinic I, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
    • ,
  • Katrin Müller

      Affiliations

    • Medical Clinic I, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
    • ,
  • Martin Bornhäuser

      Affiliations

    • DFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany
    • Medical Clinic I, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
    • ,
  • Martin Ryser

      Affiliations

    • Department of Pediatrics, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
    • Drs. Ryser and Brenner contributed equally to this work.
    • ,
  • Sebastian Brenner

      Affiliations

    • Department of Pediatrics, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
    • DFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany
    • Drs. Ryser and Brenner contributed equally to this work.
    • Corresponding Author InformationOffprint requests to: Sebastian Brenner, M.D., Department of Pediatrics, University Clinic Carl Gustav Carus Dresden, Building 21, Fetscherstr 74, 01307 Dresden, Germany

Received 15 June 2009 ,Revised 13 December 2009 ,Accepted 14 December 2009.

References 

  1. Gilliland DG. FLT3-activating mutations in acute promyelocytic leukaemia: A rationale for risk-adapted therapy with FLT3 inhibitors. Best Pract Res Clin Haematol. 2003;16:409–417
  2. Lee BH, Tothova Z, Levine RL, et al. FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell. 2007;12:367–380
  3. Mizuki M, Fenski R, Halfter H, et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000;96:3907–3914
  4. Kiyoi H, Naoe T, Nakano Y, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93:3074–3080
  5. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–4335
  6. Matsunaga T, Takemoto N, Sato T, et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med. 2003;9:1158–1165
  7. Tavor S, Petit I, Porozov S, et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res. 2004;64:2817–2824
  8. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006;12:1167–1174
  9. Broxmeyer HE, Kohli L, Kim CH, et al. Stromal cell-derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and G[alpha]i proteins and enhances engraftment of competitive, repopulating stem cells. J Leukoc Biol. 2003;73:630–638
  10. Zeng Z, Shi YX, Samudio IJ, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood. 2009;113:6215–6224
  11. Liesveld JL, Bechelli J, Rosell K, et al. Effects of AMD3100 on transmigration and survival of acute myelogenous leukemia cells. Leuk Res. 2007;31:1553–1563
  12. Juarez J, Dela PA, Baraz R, et al. CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia. 2007;21:1249–1257
  13. Nervi B, Ramirez P, Rettig MP, et al. Chemosensitization of acute myeloid leukemia [AML] following mobilization by the CXCR4 antagonist AMD3100. Blood. 2009;113:6206–6214
  14. Rombouts EJ, Pavic B, Lowenberg B, Ploemacher RE. Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood. 2004;104:550–557
  15. Fukuda S, Broxmeyer HE, Pelus LM. Flt3 ligand and the Flt3 receptor regulate hematopoietic cell migration by modulating the SDF-1alpha[CXCL12]/CXCR4 axis. Blood. 2005;105:3117–3126
  16. Koch S, Jacobi A, Ryser M, Ehninger G, Thiede C. Abnormal localization and accumulation of FLT3-ITD, a mutant receptor tyrosine kinase involved in leukemogenesis. Cells Tissues Organs. 2008;188:225–235
  17. Brenner S, Whiting-Theobald NL, Linton GF, et al. Concentrated RD114-pseudotyped MFGS-gp91phox vector achieves high levels of functional correction of the chronic granulomatous disease oxidase defect in NOD/SCID/beta- microglobulin-/- repopulating mobilized human peripheral blood CD34+ cells. Blood. 2003;102:2789–2797
  18. Brenner S, Ryser MF, Whiting-Theobald NL, Gentsch M, Linton GF, Malech HL. The late dividing population of gamma-retroviral vector transduced human mobilized peripheral blood progenitor cells contributes most to gene-marked cell engraftment in nonobese diabetic/severe combined immunodeficient mice. Stem Cells. 2007;25:1807–1813
  19. Jo DY, Rafii S, Hamada T, Moore MA. Chemotaxis of primitive hematopoietic cells in response to stromal cell-derived factor-1. J Clin Invest. 2000;105:101–111
  20. Soriano SF, Hernanz-Falcon P, Rodriguez-Frade JM, et al. Functional inactivation of CXC chemokine receptor 4-mediated responses through SOCS3 up-regulation. J Exp Med. 2002;196:311–321
  21. Fukuda S, Pelus LM. Internal tandem duplication of Flt3 modulates chemotaxis and survival of hematopoietic cells by SDF1alpha but negatively regulates marrow homing in vivo. Exp Hematol. 2006;34:1041–1051
  22. Pello OM, Moreno-Ortiz MC, Rodríguez-Frade JM, et al. SOCS up-regulation mobilizes autologous stem cells through CXCR4 blockade. Blood. 2006;108:3928–3937
  23. Choudhary C, Brandts C, Schwable J, et al. Activation mechanisms of STAT5 by oncogenic Flt3-ITD. Blood. 2007;110:370–374
  24. Schuringa JJ, Wierenga AT, Kruijer W, et al. Constitutive Stat3, Tyr705, and Ser727 phosphorylation in acute myeloid leukemia cells caused by the autocrine secretion of interleukin-6. Blood. 2000;95:3765–3770
  25. Mizuki M, Fenski R, Halfter H, et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000;96:3907–3914
  26. Tavor S, Eisenbach M, Jacob-Hirsch J, et al. The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation. Leukemia. 2008;22:5151–5158
  27. Fierro FA, Brenner S, Oelschlaegel U, et al. Combining SDF-1/CXCR4 antagonism and chemotherapy in relapsed acute myeloid leukemia. Leukemia. 2008;23:393–396
  28. Hendrix CW, Collier AC, Lederman MM, et al. Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection. J Acquir Immune Defic Syndr. 2004;37:1253–1262

PII: S0301-472X(09)00460-3

doi: 10.1016/j.exphem.2009.12.003

Experimental Hematology
Volume 38, Issue 3 , Pages 180-190 , March 2010

Article Tools

* Image Usage & Resolution