Cytosine-arabinoside stimulates the capability of human marrow stromal cells to support normal hematopoiesis.

Abstract

Background: Acute leukemia (AL) is characterized by overgrowth of neoplastic hematopoietic precursor cells in the bone marrow. After successful chemotherapy in patients with AL, the growth of leukemic cell is thought to be replaced by the recovery of normal hematopoietic cells as a consequence of the activity of anti-cancer agents in eradicating all hematopoietic cells, whether or not they are leukemic cells. However, little is known about the effects of anti-cancer agents on marrow stromal cells, which play a crucial role in supporting hematopoietic cell development. In the present study, we investigated the direct activity of cytosine arabinoside (Ara-C), a key drug for treatment of AL, on human non-leukemic marrow stromal cells by analyzing the effect of Ara-C on gene expression.

Methods: Stromal cells were established from 11 patients with no neoplastic hematopoietic precursor cells in the bone marrow. The cells were treated with Ara-C for one week, co-cultured with allogeneic CD34-positive cells, and subjected to colony assay to evaluate their supportive function. A genome-wide DNA microarray analysis was performed to determine Ara-C-induced changes in gene expression in the stromal cells.

Results: Treatment of the stromal cells with Ara-C resulted in a dose-dependent increase in their supportive function. These effects were more evident in the late phase than in the early phase of co-culture with CD34-positive cells, suggesting that Ara-C-treated stromal cells preferably support very immature cells, rather than committed progenitor cells. Furthermore, gene expression profiling with DNA microarrays revealed prominent up-regulation of growth-differentiation factor 15 (GDF15), a divergent member of the transforming growth factor beta superfamily, with concomitant down-regulation of colony-stimulating factor 1 receptor (CSF-1R), both of which are predominantly expressed on macrophages.

Conclusions: Our present study demonstrated that Ara-C directly enhanced the ability of stromal cells to support the development of immature hematopoietic cells, possibly by modulating the function of macrophages in the bone marrow microenvironment. This novel action of Ara-C in the marrow microenvironment may contribute to the better understanding and management of chemotherapy for AL.