The oncoprotein MLL-ENL disturbs hematopoietic lineage determination and transforms a biphenotypic lymphoid/myeloid cell.
Mixed-lineage leukemia (MLL) fusion proteins are associated with a unique class of leukemia that is characterized by the simultaneous expression of lymphoid-specific as well as myeloid-specific genes. Here we report the first experimental model of MLL. Murine bone marrow cells were retrovirally transduced to express the MLL-eleven nineteen leukemia (MLL-ENL) fusion protein. When cultivated in flt-3 ligand, stem cell factor and interleukin-7 (IL-7) in a stroma-free culture system MLL-ENL-transduced as well as control cells showed a wave of B-lymphopoiesis. Whereas the controls exhausted their proliferative capacity in a CD19+/B220+ state, a continuously proliferating CD19-/B220+ cell population emerged in the MLL-ENL-transduced cultures. Despite the lymphoid surface marker, these cells were of monocytoid morphology. The immortalized cells contained unrearranged retrovirus, expressed MLL-ENL mRNA and were able to grow in syngenic recipients. From the diseased animals an MLL-ENL positive, B220+/CD19- cell type could be reisolated and cultivated in vitro. In analogy to human MLL, MLL-ENL-transformed cells not only coexpressed lymphocyte-specific (rag1, rag2, pax5, Tdt) and monocyte-specific genes (lysozyme, c-fms), but also showed rearrangements of the genomic immunoglobulin locus. This model shows that MLL-ENL influences events of early lineage determination and it will enable the investigation of the underlying molecular processes.
Zeisig
B B
BB
Department of Genetics, University of Erlangen, Germany.
García-Cuéllar
M P
MP
Winkler
T H
TH
Slany
R K
RK
D016475:3T3 Cells; D000818:Animals; D015139:Blotting, Southern; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C425207:MLL-ENL oncoprotein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein