Abstract
The t(4;11)(q21;q23) fuses MLL to AF4, the most common MLL-fusion partner. Here we show hat MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34+ cells and generating a faithful model of t(4;11) proB 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 who evaded CD19-directed therapy by undergoing myeloid-lineage switch. Our model provides a valuable tool to unravel the pathogenesis of MLL-AF4 leukemogenesis.
Original language | English |
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Pages (from-to) | 737–749 |
Number of pages | 13 |
Journal | Cancer Cell |
Volume | 30 |
Issue number | 5 |
DOIs | |
Publication status | Published - 14 Nov 2016 |
Keywords
- MLL-AF4
- acute lymphoblastic leukemi
- chimeric fusion proteins
- mouse models of cancer
- acquired resistance to targeted therapy
- species specificity of oncogenes