Bcl-2 and its homologue, bcl-xL, encode membrane-associated proteins that suppress programmed cell death of hematopoietic cell lines after growth factor withdrawal, and are expressed in hematopoietic precursor cells. To better understand the maintenance of long-term survival in the hematopoietic stem cell population, we evaluated the expression patterns of Bcl-2 and Bcl-x in primitive hematopoietic precursor populations. Hematopoietic precursor cells expressing CD34 (CD34+) and lacking maturation-linked surface antigens (lin-) were isolated from adult human bone marrow using two-color immunofluorescence cell sorting and fractionated on the basis of forward light scatter characteristics into blast-sized and small to medium lymphocyte-sized cell populations. Bcl-2 expression was shown in 78% to 90% of CD34+ lin- blast-sized cells versus less than 10% of small to medium lymphocyte-sized CD34+ lin- cells by immunohistochemical analysis. Small to medium lymphocyte- sized CD34+ lin- cells were further enriched for primitive precursors by selecting cells that lacked expression of CD38 (CD34+ lin- CD38-). In parallel experiments, only 1% to 4% of CD34+ lin- CD38- cells expressed Bcl-2, whereas 45% to 56% of these cells generated colony- forming cells. In contrast, > or = 94% of cells in all bone marrow subpopulations studied expressed Bcl-x protein. Both alternatively spliced bcl-x transcripts, bcl-xL and bcl-xs, were present. Our data show that the most primitive hematopoietic precursors express Bcl-x but not Bcl-2. Thus, the functional bcl-2 homologue, bcl-xL, may be essential for the long-term survival of the hematopoietic stem cell population.

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