Bone marrow function following chemotherapy
Bone Marrow Function Following Chemotherapy
A critical element of patient outcome following bone marrow transplantation is efficient recovery of hematopoiesis. We have a long standing interest in understanding the influence of aggressive chemotherapy, often used clinically prior to transplant, on a patient's bone marrow capacity to support this recovery. We have identified disruption of stromal and osteoblast expression of VCAM-1, CXCL-12, and a variety of other factors required for either stem cell or committed progenitor cell chemotaxis, survival, and differentiation. These disruptions have various upstream causes including deregulation of p65 influencing VCAM-1 expression and activation of MMP-2 by chemotherapy resulting in cleavage of CXCL-12 chemokine. We have also described increased levels of bioavailable TGF-beta subsesequent to stromal cell exposure to specific chemotherapeutic agents, with neutralization of TGF-beta restoring the ability of treated stromal cell to support pro-B cell survival and expansion. We are increasingly focused on the damage that may result in reduced microenvironment support of hematopoietic stem cells and current models include both murine and human cells for ongoing work. This work is currently supported by the Heart, Lung, and Blood Institute of the NIH.