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 Blood, 15 January 2009, Vol. 113, No. 3, pp. 649-658.
Prepublished online as a Blood First Edition Paper on October 22, 2008; DOI 10.1182/blood-2008-04-152686.

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MYELOID NEOPLASIA

Stroma-dependent apoptosis in clonal hematopoietic precursors correlates with expression of PYCARD

Andrew J. Mhyre1, A. Mario Marcondes1,2, Emily Y. Spaulding1, and H. Joachim Deeg1,3

1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and Departments of 2 Pathology and 3 Medicine, University of Washington, Seattle

The role of the marrow microenvironment in the pathophysiology of myelodysplastic syndromes (MDSs) remains controversial. Using stromal/hematopoietic cell cocultures, we investigated the effects of stroma-derived signals on apoptosis sensitivity in hematopoietic precursors. The leukemia-derived cell line KG1a is resistant to proapoptotic ligands. However, when cocultured with the human stromal cell line HS5 (derived from normal marrow) and exposed to tumor necrosis factor-{alpha} (TNF-{alpha}), KG1a cells showed caspase-3 activation and induction of apoptosis. Apoptosis was contact dependent. Identical results were obtained in coculture with primary stroma. Gene-expression profiling of KG1a cells identified coculture-induced up-regulation of various genes involved in apoptosis, including PYCARD. Suppression of PYCARD expression in KG1a by miRNA interfered with apoptosis. Knockdown of the TNF receptor 1 (TNFR1) or TNFR2 in HS5 cells had no effect. However, knockdown of R1 in KG1a cells prevented TNF-{alpha}–induced apoptosis, while apoptosis was still induced by TNF-{alpha}–related apoptosis-inducing ligand. Primary CD34+ cells from MDS marrow, when cocultured with HS5 and TNF-{alpha}, also underwent apoptosis. In contrast, no apoptosis was observed in CD34+ cells from the marrow of healthy donors. These data indicate that stroma may convey not only protective effects on hematopoietic cells, but, dependent upon the milieu, may also facilitate apoptosis.


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