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Survival of chronic lymphocytic leukemia cells: CD40L and the vascular endothelial growth factor (VEGF) connection

Leukemia volume 19, pages 531–532 (2005)Cite this article

This commentary is based on the report in this issue of Leukemia by Farahani et al.1 Chronic lymphocytic leukemia (CLL), while touted as the most common adult leukemia in the Western world2, 3 is better characterized as a hematological malignancy characterized by accumulation of lymphocytes that do not like to undergo apoptosis. This apoptosis resistance is multifactorial and is influenced by cytokines, stromal environment and genetic defects acquired by the malignant B cell clone.4 The complexity of these interactions demand that we identify those mechanisms that are most critical to the apoptosis resistance of CLL B cells. In recent years, several newer insights into the immunobiology of this disease that could be manipulated to therapeutic advantage have been described. Two of these involve the CD40–CD40 ligand interaction5 and a VEGF-based autocrine pathway.6 One of the pathways responsible for the prolonged survival of CLL B Cells involves the interactions between CD40 and its ligand, CD40L (also designated as CD154). CD154 is expressed on activated T lymphocytes, macrophages and platelets,7 while CD40 is expressed on both normal B-lymphocytes and the leukemic B cells of B-CLL patients.8, 9, 10 The cognate recognition of CD40L by CD40 on the CLL B cell membrane results in a strong signal for survival. Since this interaction is likely to occur in widespread tissue microenvironments11 and is also linked to drug resistance,12, 13 any further insight into the exact mechanism of CD40 induced apoptosis resistance is valuable. The effect of CD40–CD40L interaction on survival is different in normal B-cells as compared with B-CLL cells, reported recently by gene microarray data14 and may have important therapeutic implications. In this study, Gricks et al. show and confirm prior observations that upon CD40 stimulation of B-CLL cells, there is upregulation of genes involved in survival, but also of those genes that regulate growth and proliferation of the cells negatively.

Vascular endothelial growth factor (VEGF), its isotypes and various receptors (VEGFR) play a central role in tumor angiogenesis. Since the seminal work of Dr Folkman in 1971, it is now recognized that neovascularization and angiogenic switching is crucial to disease progression and metastases in solid tumors.15 Importantly, the latter phenomenon now appears linked to human leukemias as well.16, 17, 18, 19, 20 Owing to this expanding knowledge, where the VEGF–VEGFR pathway is assigned an important role in tumor survival and growth, there is a growing interest in developing antiangiogenic therapies in human leukemias. Recently, the FDA approved an antiangiogenic therapy for the treatment of metastatic colorectal cancer.21 This is a humanized monoclonal antibody, which is directed against VEGF. Importantly, VEGF is also considered to be a survival factor for leukemic CLL B cells.22, 23 Expression of VEGF, its receptor/s and increased microvessel density for both marrow and lymph nodes sites have all been reported in CLL.24, 25, 26

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  1. Mayo Clinic, Rochester, MN, USA

    N E Kay

  2. Long Island Jewish Medical Center, New Hyde Park, NY, USA

    T Wasil

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Kay, N., Wasil, T. Survival of chronic lymphocytic leukemia cells: CD40L and the vascular endothelial growth factor (VEGF) connection. Leukemia 19, 531–532 (2005). https://doi.org/10.1038/sj.leu.2403677

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