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The t(4;11)(q21;q23) fuses mixed-lineage leukemia (MLL) to AF4, the most common MLL-fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34(+) cells, thereby generating a model of t(4;11) pro-B acute lymphoblastic leukemia (ALL) that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a B ALL distinct from MLL-AF9 through differential genomic target binding of the fusion proteins leading to specific gene expression patterns. MLL-Af4 cells can assume a myeloid state under environmental pressure but retain lymphoid-lineage potential. Such incongruity was also observed in t(4;11) patients in whom leukemia evaded CD19-directed therapy by undergoing myeloid-lineage switch. Our model provides a valuable tool to unravel the pathogenesis of MLL-AF4 leukemogenesis.

Original publication

DOI

10.1016/j.ccell.2016.10.008

Type

Journal article

Journal

Cancer Cell

Publication Date

14/11/2016

Volume

30

Pages

737 - 749

Keywords

MLL-AF4, acquired resistance to targeted therapy, acute lymphoblastic leukemia, chimeric fusion proteins, mouse models of cancer, species specificity of oncogenes, Animals, Antigens, CD34, Cell Lineage, Cell Transformation, Neoplastic, Disease Models, Animal, Drug Resistance, Neoplasm, Histone-Lysine N-Methyltransferase, Humans, Mice, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Translocation, Genetic