Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells

Abstract

IntroductionB-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of a monoclonal population of CD5 ϩ neoplastic B cells in secondary lymphoid organs, marrow, and blood. Because most of the circulating leukemia cells are arrested in the G 0 /G 1 phase of the cell cycle, the primary defect may be one of resistance to programmed cell death rather than accelerated cell division. 1,2 However, CLL cells can rapidly undergo spontaneous apoptosis under culture conditions that support the growth of human B-cell lines. This implies that such ex vivo conditions lack factors necessary for leukemia cell survival or that the resistance to apoptosis is not intrinsic to the leukemia B cell.The leukemia cell microenvironment in the marrow or in secondary lymphoid tissues may contribute to the noted resistance of CLL cells to apoptosis in vivo. 3,4 Normal B-cell development depends on complex interactions with accessory cells that define the so-called specialized microenvironments. T cells and a variety of different types of adherent cells, generally defined as stromal cells, are the main elements of the microenvironment. 3 In patients with CLL, the marrow invariably is infiltrated with CLL B cells, and the pattern and extent of marrow involvement correlates with clinical stage and prognosis. 5,6 As such, interactions with stromal cells in the marrow microenvironment appear to play a role in disease progression and resistance to therapy. [7][8][9] In addition, we found that a small proportion of the mononuclear cells from the blood of patients with CLL can differentiate into large, round, adherent cells that attract CLL cells and protect them from undergoing spontaneous or drug-induced cell death. 10,11 Because these cells share features with thymic nurse cells that nurture developing thymocytes, we designated them nurselike cells (NLCs). Although NLCs differentiate from blood mononuclear cells after several days in vitro, fully differentiated NLCs can be found in the spleen and secondary lymphoid tissue of patients with CLL, 11 where they might play a role in protecting CLL cells from apoptosis in vivo. This model implies that CLL cells depend on specific extrinsic factors from NLCs and other stromal elements for their survival. Conceivably, CLL cells recirculate from the blood through secondary lymphoid tissues and back into the systemic circulation in response to certain chemokines.One such chemokine is stromal cell-derived factor-1/pre-B cell growth-stimulating factor (SDF-1/PBSF), which recently has been designated CXCL12. CXCL12 is a member of a family of chemotactic cytokines (chemokines) that initially were characterized as growth-stimulating factors for B-cell precursors. 12 CXCR4 is a primary physiologic receptor for CXCL12 and functions as a coreceptor for entry of T-tropic strains of HIV-1. Mutant mice with targeted gene disruption of CXCL12 or CXCR4 have defects in the We previously demonstrated that stromal cells can attract CLL cells through the production of CXCL12. 13 In addition, NLCs e...

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…We demonstrated earlier that CXCR4 antagonists effectively block CXCL12-induced activation, migration and signaling of CLL cells. 54 Also, CXCR4 antagonists reversed stromal cell-mediated protection from spontaneous or fludarabine-induced apoptosis of CLL cells, suggesting a potential role of CXCR4 antagonists in combination with a B-celltargeted therapy in the treatment of CLL. Because of the high-level CXCR4 expression, and the particular requirement of stromal cell support for CLL cell survival, it appears that CLL patients would particularly respond to CXCR4 antagonists.…”

“…Nonspecific and specific CXCR4 antagonists, such as pertussis toxin and CXCR4 antagonists (T140 and AMD3100) can block this adhesion and migration. 51 Adhesion to stromal cells confers resistance to spontaneous and drug-induced cell death of tumor cells, and therefore is also termed cell adhesion-mediated drug resistance. 52,53 Tumor cells that adhere to stromal cells through CXCR4 are therefore, at least partially, protected from the effects of cytotoxic chemotherapy and represent a reservoir for minimal residual disease (MRD) and relapses commonly seen in the treatment of patients with various cancers.…”

“…However, the overall role of MSC in the tumor microenvironment remains controversial. Although on the one hand, MSC can provide survival, growth and drug resistance signals, 48,54 MSC can also induce cell cycle and growth arrest in epithelial cancer [55][56][57] and leukemia cells. 58 On the basis of these findings, the therapeutic use of MSC to decelerate tumor growth has been proposed.…”

Homing of Cancer Cells to the Bone

“…In chronic lymphoblastic leukemia, coculture with SDF-1 induces chemotaxis to stromal cells in vitro [85]. Small peptide CXCR4 antagonists effectively blocks SDF-1 induced migration [86].…”

A novel role of the CX3CR1/CX3CL1 system in the cross-talk between chronic lymphocytic leukemia cells and tumor microenvironment

“…11 Finally, migration of CLL cells to bone marrow is mediated by CXCR4, highly expressed in leukemic cells, and its ligand CXCL12, produced by stromal cells. 12 CX 3 CL1/fractalkine, a chemokine constitutively expressed by many hematopoietic and non-hematopoietic tissues, 13,14 is synthesized as membrane-bound protein but can also be released by proteolytic cleavage. Membrane-bound CX 3 CL1 functions as an adhesion molecule whereas the secreted form triggers chemotaxis of lymphocytes and monocytes to inflammatory sites.…”