The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
권호 표지
DOI QR코드

DOI QR Code

Targeting the CXCL12/CXCR4 axis in acute myeloid leukemia: from bench to bedside

  • Cho, Byung-Sik (Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, Leukemia Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Kim, Hee-Je (Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, Leukemia Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Konopleva, Marina (Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center)
  • Received : 2016.07.25
  • Accepted : 2017.02.08
  • Published : 2017.03.01
⟨ Previous Next ⟩

Abstract

The interactions between the cancerous cells of acute myeloid leukemia (AML) and the bone marrow (BM) microenvironment have been postulated to be important for resistance to chemotherapy and disease relapse in AML. The chemokine receptor CXC chemokine receptor 4 (CXCR4) and its ligand, CXC motif ligand 12 (CXCL12), also known as stromal cell-derived factor $1{\alpha}$, are key mediators of this interaction. CXCL12 is produced by the BM microenvironment, binds and activates its cognate receptor CXCR4 on leukemic cells, facilitates leukemia cell trafficking and homing in the BM microenvironment, and keeps leukemic cells in close contact with the stromal cells and extracellular matrix that constitutively generate growth-promoting and anti-apoptotic signals. Indeed, a high level of CXCR4 expression on AML blasts is known to be associated with poor prognosis. Recent preclinical and clinical studies have revealed the safety and potential clinical utility of targeting the CXCL12/CXCR4 axis in AML with different classes of drugs, including small molecules, peptides, and monoclonal antibodies. In this review, we describe recent evidence of targeting these leukemia-stroma interactions, focusing on the CXCL12/CXCR4 axis. Related early phase clinical studies will be also introduced.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

References

  1. Estey E, Dohner H. Acute myeloid leukaemia. Lancet 2006;368:1894-1907. https://doi.org/10.1016/S0140-6736(06)69780-8
  2. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010;363:2424-2433. https://doi.org/10.1056/NEJMoa1005143
  3. Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012;481:506-510. https://doi.org/10.1038/nature10738
  4. 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. https://doi.org/10.1182/blood-2008-06-162123
  5. 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. https://doi.org/10.1182/blood-2008-05-158311
  6. Peled A, Tavor S. Role of CXCR4 in the pathogenesis of acute myeloid leukemia. Theranostics 2013;3:34-39. https://doi.org/10.7150/thno.5150
  7. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 2006;25:977-988. https://doi.org/10.1016/j.immuni.2006.10.016
  8. Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 2010;16:2927-2931. https://doi.org/10.1158/1078-0432.CCR-09-2329
  9. Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK. CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin Cancer Res 2011;17:2074-2080. https://doi.org/10.1158/1078-0432.CCR-10-2636
  10. Greenbaum A, Hsu YM, Day RB, et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 2013;495:227-230. https://doi.org/10.1038/nature11926
  11. Zhang Y, Patel S, Abdelouahab H, et al. CXCR4 inhibitors selectively eliminate CXCR4-expressing human acute myeloid leukemia cells in NOG mouse model. Cell Death Dis 2012;3:e396. https://doi.org/10.1038/cddis.2012.137
  12. Chen Y, Jacamo R, Konopleva M, Garzon R, Croce C, Andreeff M. CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia. J Clin Invest 2013;123:2395-2407. https://doi.org/10.1172/JCI66553
  13. Mohle R, Bautz F, Rafii S, Moore MA, Brugger W, Kanz L. The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1. Blood 1998;91:4523-4530.
  14. Voermans C, van Heese WP, de Jong I, Gerritsen WR, van Der Schoot CE. Migratory behavior of leukemic cells from acute myeloid leukemia patients. Leukemia 2002;16:650-657. https://doi.org/10.1038/sj.leu.2402431
  15. 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. https://doi.org/10.1182/blood-2004-02-0566
  16. Konoplev S, Rassidakis GZ, Estey E, et al. Overexpression of CXCR4 predicts adverse overall and event-free survival in patients with unmutated FLT3 acute myeloid leukemia with normal karyotype. Cancer 2007;109:1152-1156. https://doi.org/10.1002/cncr.22510
  17. Spoo AC, Lubbert M, Wierda WG, Burger JA. CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood 2007;109:786-791. https://doi.org/10.1182/blood-2006-05-024844
  18. Dommange F, Cartron G, Espanel C, et al. CXCL12 polymorphism and malignant cell dissemination/tissue infiltration in acute myeloid leukemia. FASEB J 2006;20:1913-1915. https://doi.org/10.1096/fj.05-5667fje
  19. Fiegl M, Samudio I, Clise-Dwyer K, Burks JK, Mnjoyan Z, Andreeff M. CXCR4 expression and biologic activity in acute myeloid leukemia are dependent on oxygen partial pressure. Blood 2009;113:1504-1512.
  20. Sison EA, McIntyre E, Magoon D, Brown P. Dynamic chemotherapy-induced upregulation of CXCR4 expression: a mechanism of therapeutic resistance in pediatric AML. Mol Cancer Res 2013;11:1004-1016. https://doi.org/10.1158/1541-7786.MCR-13-0114
  21. 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. https://doi.org/10.1158/0008-5472.CAN-03-3693
  22. 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. https://doi.org/10.1016/j.leukres.2007.02.017
  23. 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;22:2151-5158. https://doi.org/10.1038/leu.2008.238
  24. Oishi S, Fujii N. Peptide and peptidomimetic ligands for CXC chemokine receptor 4 (CXCR4). Org Biomol Chem 2012;10:5720-5731. https://doi.org/10.1039/c2ob25107h
  25. Beider K, Begin M, Abraham M, et al. CXCR4 antagonist 4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth. Exp Hematol 2011;39:282-292. https://doi.org/10.1016/j.exphem.2010.11.010
  26. Cho BS, Zeng Z, Mu H, et al. Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy. Blood 2015;126:222-232. https://doi.org/10.1182/blood-2015-02-628677
  27. Kuhne MR, Mulvey T, Belanger B, et al. BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies. Clin Cancer Res 2013;19:357-366. https://doi.org/10.1158/1078-0432.CCR-12-2333
  28. Peng SB, Zhang X, Paul D, et al. Inhibition of CXCR4 by LY2624587, a fully humanized anti-CXCR4 antibody induces apoptosis of hematologic malignancies. PLoS One 2016;11:e0150585. https://doi.org/10.1371/journal.pone.0150585
  29. Pernasetti F, Liu SH, Hallin M, et al. A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematological malignancies. Blood 2014;124:2311.
  30. Zhang Y, Saavedra E, Tang R, et al. Targeting acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)in NOD/SCID mice. Blood 2015;126:1362.
  31. Hsieh YT, Jiang E, Pham J, et al. VLA4 blockade in acute myeloid leukemia. Blood 2013;122:3944.
  32. Layani-Bazar A, Skornick I, Berrebi A, et al. Redox modulation of adjacent thiols in VLA-4 by AS101 converts myeloid leukemia cells from a drug-resistant to drug-sensitive state. Cancer Res 2014;74:3092-3103. https://doi.org/10.1158/0008-5472.CAN-13-2159
  33. Chien S, Haq SU, Pawlus M, et al. Adhesion of acute myeloid leukemia blasts to E-selectin in the vascular niche enhances their survival by mechanisms such as Wnt activation. Blood 2013;122:61. https://doi.org/10.1182/blood-2012-12-473389
  34. 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. https://doi.org/10.1038/nm1483
  35. Jacamo R, Chen Y, Wang Z, et al. Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-kappaB mediates chemoresistance. Blood 2014;123:2691-2702. https://doi.org/10.1182/blood-2013-06-511527
  36. Klein RS, Rubin JB. Immune and nervous system CXCL12 and CXCR4: parallel roles in patterning and plasticity. Trends Immunol 2004;25:306-314. https://doi.org/10.1016/j.it.2004.04.002
  37. Han AR, Lee JY, Kim HJ, Min WS, Park G, Kim SH. A CXCR4 antagonist leads to tumor suppression by activation of immune cells in a leukemia-induced microenvironment. Oncol Rep 2015;34:2880-2888. https://doi.org/10.3892/or.2015.4297
  38. Hoellenriegel J, Zboralski D, Maasch C, et al. The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization. Blood 2014;123:1032-1039. https://doi.org/10.1182/blood-2013-03-493924
  39. Vater A, Sahlmann J, Kroger N, et al. Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in-class mirror-image oligonucleotide inhibitor of CXCL12. Clin Pharmacol Ther 2013;94:150-157. https://doi.org/10.1038/clpt.2013.58
  40. Uy GL, Rettig MP, Motabi IH, et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood 2012;119:3917-3924. https://doi.org/10.1182/blood-2011-10-383406
  41. Greenberg PL, Lee SJ, Advani R, et al. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol 2004;22:1078-1086. https://doi.org/10.1200/JCO.2004.07.048
  42. Uy GL, Avigan D, Cortes JE, et al. Safety and tolerability of plerixafor in combination with cytarabine and daunorubicin in patients with newly diagnosed acute myeloid leukemia: preliminary results from a phase I study. Blood 2011;118:82. https://doi.org/10.1182/blood-2011-05-352708
  43. Roboz GJ, Scandura JM, Ritchie E, et al. Combining decitabine with plerixafor yields a high response rate in newly diagnosed older patients with AML. Blood 2013;122:621. https://doi.org/10.1182/blood-2013-06-508507
  44. Andreeff M, Zeng Z, Kelly M, et al. Mobilization and elimination of FLT3-ITD+ acute myelogenous leukemia (AML) stem/progenitor cells by plerixafor, G-CSF, and sorafenib: phase I trial results in relapsed/refractory AML patients. J Clin Oncol 2014;32(15 Suppl):7033.
  45. Borthakur G, Ofran Y, Nagler A, et al. The peptidic CXCR4 antagonist, BL-8040, significantly reduces bone marrow immature leukemia progenitors by inducing differentiation, apoptosis and mobilization: results of the dose escalation clinical trial in acute myeloid leukemia. Blood 2015;126:2546.
  46. Becker PS, Foran JM, Altman JK, et al. Targeting the CXCR4 pathway: safety, tolerability and clinical activity of ulocuplumab (BMS-936564), an anti-CXCR4 antibody, in relapsed/refractory acute myeloid leukemia. Blood 2014;124:386.
  47. Rashidi A, DiPersio JF. Targeting the leukemia-stroma interaction in acute myeloid leukemia: rationale and latest evidence. Ther Adv Hematol 2016;7:40-51. https://doi.org/10.1177/2040620715619307

Cited by

  1. The role of hypoxia on the acquisition of epithelial-mesenchymal transition and cancer stemness: a possible link to epigenetic regulation vol.32, pp.4, 2017, https://doi.org/10.3904/kjim.2016.302
  2. Cancer Cells Exploit Notch Signaling to Redefine a Supportive Cytokine Milieu vol.9, pp.None, 2017, https://doi.org/10.3389/fimmu.2018.01823
  3. Adhesion Deregulation in Acute Myeloid Leukaemia vol.8, pp.1, 2019, https://doi.org/10.3390/cells8010066
  4. Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging vol.97, pp.2, 2017, https://doi.org/10.1111/imcb.12216
  5. 3D models of the bone marrow in health and disease: yesterday, today, and tomorrow vol.9, pp.1, 2017, https://doi.org/10.1557/mrc.2018.203
  6. Alteration of cellular and immune‐related properties of bone marrow mesenchymal stem cells and macrophages by K562 chronic myeloid leukemia cell derived exosomes vol.234, pp.4, 2017, https://doi.org/10.1002/jcp.27142
  7. Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma vol.104, pp.4, 2017, https://doi.org/10.3324/haematol.2017.180505
  8. High Constitutive Cytokine Release by Primary Human Acute Myeloid Leukemia Cells Is Associated with a Specific Intercellular Communication Phenotype vol.8, pp.7, 2019, https://doi.org/10.3390/jcm8070970
  9. The FLT3-ITD mutation and the expression of its downstream signaling intermediates STAT5 and Pim-1 are positively correlated with CXCR4 expression in patients with acute myeloid leukemia vol.9, pp.1, 2017, https://doi.org/10.1038/s41598-019-48687-z
  10. The CXCR4 Antagonist, AMD3100, Reverses Mesenchymal Stem Cell-Mediated Drug Resistance in Relapsed/Refractory Acute Lymphoblastic Leukemia vol.13, pp.None, 2020, https://doi.org/10.2147/ott.s249425
  11. Targeting CXCR4 in AML and ALL vol.10, pp.None, 2017, https://doi.org/10.3389/fonc.2020.01672
  12. Overexpressed microRNA‐103a‐3p inhibits acute lower‐extremity deep venous thrombosis via inhibition of CXCL12 vol.72, pp.3, 2017, https://doi.org/10.1002/iub.2168
  13. DNA methylation disruption reshapes the hematopoietic differentiation landscape vol.52, pp.4, 2017, https://doi.org/10.1038/s41588-020-0595-4
  14. Bone marrow niches in haematological malignancies vol.20, pp.5, 2017, https://doi.org/10.1038/s41568-020-0245-2
  15. Dissecting the role of the CXCL12/CXCR4 axis in acute myeloid leukaemia vol.189, pp.5, 2017, https://doi.org/10.1111/bjh.16456
  16. Extracellular Adenine Nucleotides and Adenosine Modulate the Growth and Survival of THP-1 Leukemia Cells vol.21, pp.12, 2017, https://doi.org/10.3390/ijms21124425
  17. Has Drug Repurposing Fulfilled Its Promise in Acute Myeloid Leukaemia? vol.9, pp.6, 2020, https://doi.org/10.3390/jcm9061892
  18. Adipocytes in hematopoiesis and acute leukemia: friends, enemies, or innocent bystanders? vol.34, pp.9, 2020, https://doi.org/10.1038/s41375-020-0886-x
  19. The Role of Bone Stem Cell Niches in Bone Metastasis vol.10, pp.21, 2017, https://doi.org/10.3390/app10217713
  20. An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination vol.13, pp.1, 2017, https://doi.org/10.1186/s13045-020-00863-9
  21. Chemokine receptor CXCR4: An important player affecting the molecular-targeted drugs commonly used in hematological malignancies vol.13, pp.12, 2017, https://doi.org/10.1080/17474086.2020.1839885
  22. Importance of Altered Gene Expression of Metalloproteinases 2, 9, and 16 in Acute Myeloid Leukemia: Preliminary Study vol.2021, pp.None, 2017, https://doi.org/10.1155/2021/6697975
  23. The Dynamic Interface Between the Bone Marrow Vascular Niche and Hematopoietic Stem Cells in Myeloid Malignancy vol.9, pp.None, 2021, https://doi.org/10.3389/fcell.2021.635189
  24. The CXCL12 Crossroads in Cancer Stem Cells and Their Niche vol.13, pp.3, 2017, https://doi.org/10.3390/cancers13030469
  25. At the Bedside: Profiling and treating patients with CXCR4‐expressing cancers vol.109, pp.5, 2021, https://doi.org/10.1002/jlb.5bt1219-714r
  26. In Silico Methods for the Identification of Diagnostic and Favorable Prognostic Markers in Acute Myeloid Leukemia vol.22, pp.17, 2017, https://doi.org/10.3390/ijms22179601
  27. Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression vol.35, pp.10, 2017, https://doi.org/10.1038/s41375-021-01338-7
  28. Hematopoietic versus leukemic stem cell quiescence: Challenges and therapeutic opportunities vol.50, pp.None, 2021, https://doi.org/10.1016/j.blre.2021.100850
  29. A Role for the Bone Marrow Microenvironment in Drug Resistance of Acute Myeloid Leukemia vol.10, pp.11, 2021, https://doi.org/10.3390/cells10112833
  30. Relevance of plasma bone marrow Activin-A and CXCL-12 concentration levels as a biomarker in acute myeloid leukemia vol.32, pp.3, 2017, https://doi.org/10.3233/cbm-203171