B cells and macrophages pursue a common path toward the development and progression of chronic lymphocytic leukemia.

The development and progression of chronic B-cell tumors depend on a complex microenvironmental network of cells that include monocyte-derived macrophages. In chronic lymphocytic leukemia (CLL) the survival of malignant cells is supported in vitro by nurse-like cells, which differentiate from CD14+ monocytes and have been identified as tumor-associated macrophages (TAMs). The role of the monocyte/macrophage lineage in CLL has been extensively studied in vitro, but only recently has been investigated in in vivo models. We here discuss how the cellular and molecular interactions that physiologically occur between B cells and macrophages can be subverted in chronic B lymphoid malignancies. Clinical approaches for the therapeutic targeting of TAMs are under evaluation. Promising strategies, along with a direct impact on the malignant cells, affect crucial pathways involved in the interaction of leukemic cells with TAMs. As an example, ibrutinib reduces CLL cell chemoattraction by inhibiting macrophage secretion of CXCL13. Lenalidomide and trabectedin prevent TAM recruitment mainly through CCL2 blockade. Most advanced strategies aim at depleting macrophages by targeting the CSF1/CSF1R pathway, which is fundamental for TAM survival. Of note, CSF1 transcripts are significantly more abundant in progressive CLL patients when compared with stable CLL and the frequency of CSF1R+ TAMs correlates with poor survival in hematological malignancies. The successful combination of CSF1R inhibition with currently available agents targeting malignant cells might represent the next therapeutic frontier in CLL. Conceivably these approaches may become applicable to numerous chronic B lymphoid malignancies.

Xenograft models of chronic lymphocytic leukemia: problems, pitfalls and future directions.

Xenotransplantation of human tumor cells into immunodeficient mice has been a powerful preclinical tool in several hematological malignancies, with the notable exception of chronic lymphocytic leukemia (CLL). For several decades, this possibility was hampered by the inefficient and/or short-term engrafment of CLL cells into available animals. The development of new generations of immunocompromised mice has allowed to partially overcome these constraints. Novel humanized animal models have been created that allow to recapitulate the pathogenesis of the disease and the complex in vivo relationships between leukemic cells and the microenvironment. In this review we discuss the development of xenograft models of CLL, how they may help elucidating the mechanisms that account for the natural history of the disease and facilitating the design of novel therapeutic approaches.

An overview of chronic lymphocytic leukaemia biology.

Chronic lymphocytic leukaemia (CLL) is characterised by accumulation of CD5(+) monoclonal B cells in primary and secondary lymphoid tissues. Genetic defects and stimuli originating from the microenvironment concur to the selection and expansion of the malignant clone. Several lines of evidence, including molecular and functional analysis of the monoclonal immunoglobulin, support the hypothesis that stimulation through the B-cell receptor affects life and death of leukaemic cells. The microenvironment also has a critical role in the survival and accumulation of leukaemic cells within lymphoid organs where signals delivered from the surrounding cells are likely crucial in inducing proliferation. Nevertheless, several major biological issues still remain to be solved including regulation of the balance between proliferation and survival of leukaemic cells and the links between emerging gene abnormalities and microenvironment. In this context, mouse models are helpful tools in understanding disease mechanisms and in evaluating the efficacy of novel therapeutic agents.