BCNU-induced increase in sulfated glycosaminoglycan production by human bone marrow stromal cells

The etiology of alkylator-induced leukemia is obscure, but may be due in part to alterations in the bone marrow stromal microenvironment. Marrow extracellular matrix, including collagen, glycosaminoglycans/proteoglycans, and glycoproteins, may play a crucial role in the control of normal and abnormal hematopoiesis. Twenty-four hours after seeding, confluent human bone marrow stromal cell cultures were exposed for 3 h to 15 μg/ml of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), an alkylating agent with leukemogenic potential. On the eighth day of culture, [³⁵S]sulfate was added and radiolabeled glycosaminoglycan(s) (GAGs) was harvested 24 h later. BCNU treatment resulted in a 104% increase of the radiolabel incorporation into cetylpyridinium chloride precipitable GAG. In addition, spectrophotometric measurement of total GAG in treated cells revealed as similar GAG increase. However, BCNU treatment did not alter compartmental GAG distribution or GAG species. Our results demonstrate a profound quantitative change in the production of important extracellular matrix components by bone marrow stromal cells after exposure to a nitrosourea. This increase may be a factor in microenvironmental alterations leading to bone marrow toxicity following alkylator exposure.