Acute BCR-ABL expression during in vitro hematopoietic development of embryonic stem (ES) cells causes expansion of multipotent and myeloid progenitors with a concomitant reduction in differentiation toward erythroblasts. Progenitor cell expansion is due to a rapid, cell autonomous, suppression of programmed cell death with an increase in expression of the antiapoptotic molecule BCL-X(L). Other antiapoptotic effectors, including AKT, STAT5, and BCL-2 are not up-regulated by BCR-ABL in this system. In addition, the proapoptotic p38 mitogen-activated protein kinase (MAPK) pathway is suppressed by BCR-ABL expression in ES-derived hematopoietic progenitors. Inhibition of p38 MAPK by the small molecule inhibitor SB203580 expanded ES-derived hematopoietic progenitors by an antiapoptotic mechanism and is sufficient to expand ES-derived hematopoietic progenitors to levels approaching 80% of that seen following BCR-ABL expression. In the cellular context of ES-derived hematopoietic progenitors, BCR-ABL expression expands cells by suppressing programmed cell death with a set of antiapoptotic pathways distinct from those previously reported in continuous cell line studies.