Resistance of t(4;11) (MLL-AF4 fusion gene) leukemias to stress-induced cell death: possible mechanism for extensive extramedullary accumulation of cells and poor prognosis.
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.
University of Minnesota Cancer Center, Minneapolis 55455, USA.
J H
JH
Kersey
D
D
Wang
M
M
Oberto
D019677:Artificial Gene Fusion; D002051:Burkitt Lymphoma / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle; D002455:Cell Division; D002470:Cell Survival; D002648:Child; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D004268:DNA-Binding Proteins / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007700:Kinetics; D051788:Myeloid-Lymphoid Leukemia Protein; D009687:Nuclear Proteins / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011519:Proto-Oncogenes; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D011495:Histone-Lysine N-Methyltransferase