John C. Byrd, MD

2010-03-01

Dr. Byrd indicated no relevant conflicts of interest.

Ghosh AK, Secreto CR, Knox TR, et al. Circulating microvesicles in B cell chronic lymphocytic leukemia can stimulate marrow stromal cells: implications for disease progression. Blood. 2009. [Epub ahead of print]

Over the past decade a theme has emerged identifying the tumor microenvironment as something essential to preserving leukemia cell survival. This is particularly true in chronic lymphocytic leukemia (CLL), where spontaneous apoptosis of tumor cells occurs when the tumor cells are removed from the microenvironment. The CLL microenvironment includes a variety of different cells including mesenchymal stromal cells, macrophages, T cells, nurse-like cells, and dendritic cells. The mechanisms by which the microenvironment communicates with surrounding CLL tumor cells to promote their survival has always been presumed to occur via both release of soluble factors and direct cell-cell contact. The paper by Ghosh et al. from the Kay lab at Mayo Clinic identified a new form of communication between CLL cells and their microenvironment. They first demonstrated a difference between the type and number of circulating microvesicles in CLL patients compared to healthy volunteers. In normal subjects, the majority of microvesicles are derived from platelets, whereas in CLL patients most of the microvesicles express the B-cell antigen CD19. Microvesicles from CLL cells also appear to have a defined function. This was not shown through in vivo models but rather by utilizing well-established in vitro models. Stromal cell lines are often used as tools to mechanistically explore microenvironment and CLL tumor cell interactions. While there are many different stromal cell lines, previous studies by this same group demonstrated that the protective effect toward CLL cells appears to be similar among all those tested. They convincingly demonstrated in this paper that CLL cells, through release of microvesicles, can promote defined bone marrow stromal cell microenvironment changes. Microvesicles are specifically taken up by the stromal cells and directly activate a multitude of receptor tyrosine kinases leading to down-stream activation of the PI3-kinase pathway and paracrine secretion of VEGF and HIF1-α. Defining the exact differentiating characteristics of microvesicles between CLL patients and healthy subjects is an ongoing research effort. However, these microvesicles carry a variety of gene modifying factors, including microRNA, that exert a multitude of changes in cell function related to inhibiting both transcription and translation of specific regulatory genes within stromal cells. Although technically very challenging, it will be essential to translate this new tumor language as future studies of the CLL microenvironment progress.

This research is novel and important because it identifies a new way that CLL tumor cells communicate with the microenvironment to promote differential up-regulation of genes necessary to preserve tumor cell survival. It defines differences in tumor versus normal microenvironment that could potentially be targeted with therapeutic agents intersecting at common initiating signal transduction pathways. It also identifies a new compartment within the body to study pre-malignant to malignant transformation of CLL that could lead to a better understanding of events occurring during CLL transition to becoming more aggressive where symptoms and treatment are often necessitated.

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