Regulation of CCN2 and CCN3 in bone marrow through myloid zinc finger‐1 and its medical implication in hematopoiesis (1005.4)

Abstract

CCN2, also known as CTGF, the connective tissue growth factor, has recently been found to be in high abundance in platelets and released upon activation, an effect inhibited by aspirin, suggesting additional role in blood clotting and/or wound healing. It has been demonstrated that another member of the CCN family, the Nephroblastoma overexpressed gene (NOV, CCN3) functions in hematopoietic potential, blood cell formation, and helps to maintain a competent immune system. Taken together, these two CCN family members represent interesting new areas of research in blood cell biology, with dramatic clinical potential.Recent research in our lab discovered that the transcription factor MZF‐1 regulates both the CCN2 and CCN3 genes. Specifically, we found that MZF‐1 binds to the promoter of both CTGF (CCN2) and NOV (CCN3). It is known that both vitamin D (calcitriol) and vitamin A (all‐trans retinoic acid) stimulate transcription of the MZF1 gene. We have thus discovered a potential new pathway in which Vitamins A and D induce MZF‐1 to upregulate CCN3 and CCN2 resulting in increased hematopoietic potential and increased differentiation of HSCs and their progeny. It is known that the presence of CTGF in platelets is the result of endocytosis from extracellular environment. However, we have confirmed that treatments with either vitamin A or D activate the MZF‐1 pathway and results in increased production of CCN2 in stromal fibroblasts, which in turn results in enhanced loading of CCN2 into developing platelets in vitro.Furthermore, the regulation of CCN3 by MZF‐1 represents a testable new clinical treatment. We have observed that both vitamin A and vitamin D induce CCN3 expression, through MZF‐1, in multiple blood cell types. We are currently testing if this will lead to enhanced hematopoietic potential. This work could impact the efficacy of blood donation and transfusion, bone marrow transplants, and the treatment of bleeding and clotting diseases as well as lymphomas and leukemias.