Targeting the CXCL12/CXCR4 axis in acute myeloid leukemia: from bench to bedside
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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 1α, 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.
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 1α, 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.
참고문헌 (47)
- Estey E, "Acute myeloid leukaemia", Lancet, 368, pp.1894~1907 (2006)
- Ley TJ, "DNMT3A mutations in acute myeloid leukemia", N Engl J Med, 363, pp.2424~2433 (2010)
- Ding L, "Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing", Nature, 481, pp.506~510 (2012)
- Nervi B, "Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100", Blood, 113, pp.6206~6214 (2009)
- Zeng Z, "Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML", Blood, 113, pp.6215~6224 (2009)
- Peled A, "Role of CXCR4 in the pathogenesis of acute myeloid leukemia", Theranostics, 3, pp.34~39 (2013)
- Sugiyama T, "Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches", Immunity, 25, pp.977~988 (2006)
- Teicher BA, "CXCL12 (SDF-1)", CXCR4 pathway in cancer, 2010, pp.16, 2927~2931
- Duda DG, "CXCL12 (SDF1alpha)-CXCR4", CXCR7 pathway inhibition:an emerging sensitizer for anticancer therapies?, 2011, pp.17, 2074~2080
- Greenbaum A, "CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance", Nature, 495, pp.227~230 (2013)
- Zhang Y, "CXCR4 inhibitors selectively eliminate CXCR4-expressing human acute myeloid leukemia cells in NOG mouse model", Cell Death Dis, 3, pp.e396~ (2012)
- Chen Y, "CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia", J Clin Invest, 123, pp.2395~2407 (2013)
- Mohle R, "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, 91, pp.4523~4530 (1998)
- Voermans C, "Migratory behavior of leukemic cells from acute myeloid leukemia patients", Leukemia, 16, pp.650~657 (2002)
- Rombouts EJ, "Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia", Blood, 104, pp.550~557 (2004)
- Konoplev S, "Overexpression of CXCR4 predicts adverse overall and event-free survival in patients with unmutated FLT3 acute myeloid leukemia with normal karyotype", Cancer, 109, pp.1152~1156 (2007)
- Spoo AC, "CXCR4 is a prognostic marker in acute myelogenous leukemia", Blood, 109, pp.786~791 (2007)
- Dommange F, "CXCL12 polymorphism and malignant cell dissemination", tissue infiltration in acute myeloid leukemia, 2006, pp.20, 1913~1915
- Fiegl M, "CXCR4 expression and biologic activity in acute myeloid leukemia are dependent on oxygen partial pressure", Blood, 113, pp.1504~1512 (2009)
- Sison EA, "Dynamic chemotherapy-induced upregulation of CXCR4 expression:a mechanism of therapeutic resistance in pediatric AML", Mol Cancer Res, 11, pp.1004~1016 (2013)
- Tavor S, "CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD", SCID mice, 2004, pp.64, 2817~2824
- Liesveld JL, "Effects of AMD3100on transmigration and survival of acute myelogenous leukemia cells", Leuk Res, 31, pp.1553~1563 (2007)
- Tavor S, "The CXCR4antagonist AMD3100 impairs survival of human AML cells and induces their differentiation", Leukemia, 22, pp.2151~5158 (2008)
- Oishi S, "Peptide and peptidomimetic ligands for CXC chemokine receptor 4 (CXCR4)", Org Biomol Chem, 10, pp.5720~5731 (2012)
- Beider K, "CXCR4 antagonist 4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth", Exp Hematol, 39, pp.282~292 (2011)
- Cho BS, "Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy", Blood, 126, pp.222~232 (2015)
- Kuhne MR, "BMS-936564", MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies, 2013, pp.19, 357~366
- Peng SB, "Inhibition of CXCR4 by LY2624587, a fully humanized anti-CXCR4 antibody induces apoptosis of hematologic malignancies", PLoS One, 11, pp.e0150585~ (2016)
- Pernasetti F, "A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematological malignancies", Blood, 124, pp.2311~ (2014)
- Zhang Y, "Targeting acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)in NOD", SCID mice, 2015, pp.126, 1362~
- Hsieh YT, "VLA4 blockade in acute myeloid leukemia", Blood, 122, pp.3944~ (2013)
- Layani-Bazar A, "Redox modulation of adjacent thiols in VLA-4 by AS101 converts myeloid leukemia cells from a drug-resistant to drug-sensitive state", Cancer Res, 74, pp.3092~3103 (2014)
- Chien S, "Adhesion of acute myeloid leukemia blasts to E-selectin in the vascular niche enhances their survival by mechanisms such as Wnt activation", Blood, 122, pp.61~ (2013)
- Jin L, "Targeting of CD44 eradicates human acute myeloid leukemic stem cells", Nat Med, 12, pp.1167~1174 (2006)
- Jacamo R, "Reciprocal leukemia-stroma VCAM-1", VLA-4-dependent activation of NF-kappaB mediates chemoresistance, 2014, pp.123, 2691~2702
- Klein RS, "Immune and nervous system CXCL12and CXCR4: parallel roles in patterning and plasticity", Trends Immunol, 25, pp.306~314 (2004)
- Han AR, "A CXCR4 antagonist leads to tumor suppression by activation of immune cells in a leukemia-induced microenvironment", Oncol Rep, 34, pp.2880~2888 (2015)
- Hoellenriegel J, "The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization", Blood, 123, pp.1032~1039 (2014)
- Vater A, "Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in-class mirror-image oligonucleotide inhibitor of CXCL12", Clin Pharmacol Ther, 94, pp.150~157 (2013)
- Uy GL, "A phase 1", 2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia, 2012, pp.119, 3917~3924
- Greenberg PL, "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, 22, pp.1078~1086 (2004)
- Uy GL, "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, 118, pp.82~ (2011)
- Roboz GJ, "Combining decitabine with plerixafor yields a high response rate in newly diagnosed older patients with AML", Blood, 122, pp.621~ (2013)
- Andreeff M, "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, J Clin Oncol, pp.2014, 32(15 Suppl)[DOI]
- Borthakur G, "The peptidic CXCR4antagonist, 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, 126, pp.2546~ (2015)
- Becker PS, "Targeting the CXCR4 pathway: safety, tolerability and clinical activity of ulocuplumab (BMS-936564), an anti-CXCR4 antibody, in relapsed", refractory acute myeloid leukemia, 2014, pp.124, 386~
- Rashidi A, "Targeting the leukemia-stroma interaction in acute myeloid leukemia: rationale and latest evidence", Ther Adv Hematol, 7, pp.40~51 (2016)