ABSTRACT
Cell fusion plays a well-recognized physiological role during development, while its function during progression is still unclear. Here, we show that acute myeloid leukemia (AML) cells spontaneously fused with murine host cells in vivo. AML cells fused in most cases with mouse macrophages. Other targets of AML cell fusion were dendritic and endothelial cells. Cytogenetic and molecular analysis revealed that successive recipients conserved detectable amounts of parental DNA. Moreover, in a mouse AML1-ETO model where female AML1-ETO-leukemic cells, expressing CD45.2, were injected in congenic CD45.1 male mice AML cells, we found hybrid cells expressing both allelic types of CD45 and XXY set of sexual chromosomes. More importantly, the fusion protein AML1-ETO was transferred in the hybrid cells. When sorted hybrid cells were reinjected in a secondary recipient, they gave rise to leukemia with 100% penetrance and similar time of onset of leukemic cells. Our data indicate that in vivo fusion of cancer cells with host cells may be a mechanism of gene transfer for cancer dissemination and suggest that fused cells may be used to identify still unrecognized leukemogenic genes that are conserved in hybrid cells and able to perpetuate leukemia in vivo.
Subject(s)
Leukemia, Myeloid, Acute/metabolism , Macrophages/metabolism , Membrane Fusion , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antigens, CD34/metabolism , CD47 Antigen/immunology , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Core Binding Factor Alpha 2 Subunit/genetics , Core Binding Factor Alpha 2 Subunit/metabolism , Dendritic Cells/metabolism , Disease Models, Animal , Endothelial Cells/metabolism , Female , Hematopoietic Stem Cells/metabolism , Humans , Hyaluronan Receptors/immunology , Hybrid Cells/metabolism , Leukemia, Lymphoid/genetics , Leukemia, Lymphoid/metabolism , Leukemia, Myeloid, Acute/genetics , Male , Membrane Fusion/drug effects , Mice , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , RUNX1 Translocation Partner 1 Protein , Transcription Factors/genetics , Transcription Factors/metabolism , Transplantation, HeterologousABSTRACT
A new dic(7;12)(p12.21;p12.2) chromosome aberration was identified in an acute myeloid leukemia with FAB-M1 morphology and was cloned. Fluorescence in situ hybridization and genomic quantitative polymerase chain reaction mapping experiments revealed the precise localization of the breakpoints, at 7p12, just 5' to the GRB10 gene, and 12p11, within a genomic region containing no known genes. As a result, a new dicentric chromosome is created, dic(7;12), with the consequent deletion of 50 Mb at 7p, from the telomere to the GRB10 region, and of 30 Mb at 12p, from the telomere to p11. Several genes are included in the affected areas.
Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 7 , Leukemia, Myeloid, Acute/genetics , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , Middle Aged , Polymerase Chain ReactionABSTRACT
Rearrangement of the BCL6 gene is found in follicular lymphomas and in diffuse large B cell lymphomas of follicular center cell origin. The breakpoints cluster mainly in a region spanning the first noncoding exon of the gene (the major breakpoint region). A second breakpoint cluster has also been identified upstream of the first BCL6 noncoding exon (the alternative breakpoint region [ABR]). To date, eight different rearrangements involving the ABR have been reported. Here, we describe a novel rearrangement involving a t(2;3)(p11;q27) translocation that affects the ABR in an unusual combination with the IGK locus.
