Acute leukemias of the t(4;11) (MLL-AF4 fusion gene) type frequently have high white blood counts and extramedullary disease in multiple organs. In the present study we evaluated the hypotheses that this extensive disease is the result of extramedullary survival of leukemia cells due to resistance to stress-induced cell death. Leukemias with t(4;11)(MLL-AF4) were found to be resistant to the cell death that results from serum deprivation in vitro when compared with B lineage acute leukemias without t(4;11)(MLL-AF4). Cells with t(4;11)(MLL-AF4) did not have increased doubling time or increased numbers of cells in cycle. These results suggest that the alteration in cellular homeostasis in these leukemias is due to abnormalities of cellular destruction rather than cellular proliferation when compared to other leukemias. Our results are consistent with the hypothesis that death of non-t(4;11) leukemias occurs in the microenvironment outside of the bone marrow as a result of deficient cellular and humoral growth factors. Resistance to death signals in t(4;11) leukemias results in extensive accumulation of leukemia cells in extramedullary sites and likely contributes to the poor prognosis of these leukemias.