Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia

Abstract

Infiltration of the central nervous system is a severe trait of T cell acute lymphoblastic leukemia. Inhibition of CXC chemokine receptor 4 significantly ameliorates T cell acute lymphoblastic leukemia in murine models of the disease; however, signaling by CXC chemokine receptor 4 is important in limiting the divagation of peripheral blood mononuclear cells out of the perivascular space into the central nervous system parenchyma. Therefore, Inhibition of CXC chemokine receptor 4 potentially may untangle T cell acute lymphoblastic leukemia cells from retention outside the brain. Here, we show that leukemic lymphoblasts massively infiltrate cranial bone marrow, with diffusion to the meninges without invasion of the brain parenchyma, in mice that underwent xenotransplantation with human T cell acute lymphoblastic leukemia cells or that developed leukemia from transformed hematopoietic progenitors. We tested the hypothesis that T cell acute lymphoblastic leukemia neuropathology results from meningeal infiltration through CXC chemokine receptor 4-mediated bone marrow colonization. Inhibition of leukemia engraftment in the bone marrow by pharmacologic CXC chemokine receptor 4 antagonism significantly ameliorated neuropathologic aspects of the disease. Genetic deletion of CXCR4 in murine hematopoietic progenitors abrogated leukemogenesis induced by constitutively active Notch1, whereas lack of CCR6 and CCR7, which have been shown to be involved in T cell and leukemia extravasation into the central nervous system, respectively, did not influence T cell acute lymphoblastic leukemia development. We hypothesize that lymphoblastic meningeal infiltration as a result of bone marrow colonization is responsible for the degenerative alterations of the neuroparenchyma as well as the alteration of cerebrospinal fluid drainage in T cell acute lymphoblastic leukemia xenografts. Therefore, CXC chemokine receptor 4 may constitute a pharmacologic target for T cell acute lymphoblastic leukemia neuropathology.

Leukemia-derived exosomes and cytokines pave the way for entry into the brain

“…2,4,55 Future work is expected to shed light on the mechanistic roles for IL-15-mediated signaling in brain metastasis. In addition to the potential for an IL-15/IL-15R auto/paracrine axis, feedback loops may result in upregulation of cytokine and chemokine receptors that mediate lymphoblastic infiltration into meningeal spaces [25][26][27] and/or intracellular players that govern transmigration, such as myosin-IIA. 62 The NALM6 model may be particularly useful for understanding processes that lead to leukemia invasion of brain parenchyma, which was associated with only 10% of cases in a 1972 study of 126 autopsies.…”

“…There is intriguing evidence for the interplay between infiltrating immune cells that produce IL‐1β, TNF, or IL‐15 and other soluble factors, and the production of permeability factors (thymidine phosphorylase; TYMP, vascular endothelial growth factor‐A; VEGF‐A) by astrocytes and other resident brain cells . Also, the CXCR4 and CCR7 signaling pathways have been implicated in acute leukemia cell targeting to skull bone marrow and meningeal spaces . Emerging evidence also suggests that membrane‐bound carriers (extracellular vesicles, exosomes) released by cancer cells can mediate cell‐cell communication via the delivery of their contents, proteins, mRNAs, and microRNAs and potentially alter the microenvironment at extramedullary sites …”

“…[22][23][24] Also, the CXCR4 and CCR7 signaling pathways have been implicated in acute leukemia cell targeting to skull bone marrow and meningeal spaces. [25][26][27] Emerging evidence also suggests that membrane-bound carriers (extracellular vesicles, exosomes) released by cancer cells can mediate cell-cell communication via the delivery of their contents, proteins, mRNAs, and microRNAs [28][29][30] and potentially alter the microenvironment at extramedullary sites. 31 In this study, we address mechanisms for BCP-ALL invasion into the CNS by using a human leukemia xenograft model in NSG mice.…”

The role of ZAP70 kinase in acute lymphoblastic leukemia infiltration into the central nervous system

“…21,24 Chemokine receptors CCR7 and CXCR4 in turn have been associated with an increased capability of T-ALL cells to enter the CNS. 25,26 We hypothesized that ZAP70 mediated upregulation of CCR7 and CXCR4 may enhance the homing and the survival of CNS-prone BCP-ALL cells in the CNS niche. Downregulation of ZAP70 in 697 cells resulted in a reduced CCR7 and CXCR4 mRNA expression and a reduction of the proteins on the cell surface ( Figure 2A).…”

“…23,24 In T-cell acute lymphoblastic leukemia (T-ALL), the chemokine receptors CCR7 and CXCR4 have been associated with an increased capability of T-ALL cells to enter the CNS, mainly in cell line models. 25,26 We hypothesized that ZAP70 mediates the infiltration and the survival of ALL cells in the CNS. Downregulating ZAP70 in ALL cell lines resulted in a reduced CCR7/CXCR4 expression and an impaired CNS infiltration in NSG mice via the regulation of ERK.…”