Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Shan Lin, Roger T. Luo, Anetta Ptasinska, Jon Kerry, Salam A. Assi, Mark Wunderlich, Toshihiko Imamura, Joseph J. Kaberlein, Ahmad Rayes, Mark J. Althoff, John Anastasi, Maureen M. O'Brien, Amom Ruhikanta Meetei, Thomas A. Milne, Constanze Bonifer, James C. Mulloy, Michael J. Thirman
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.

Graphical abstract

Teaser

Lin et al. design a human MLL-mouse Af4 (MLL-Af4) fusion that can transform human CD34⁺ cells to generate pro-B acute lymphoblastic leukemia (ALL) with the characteristic features of t(4;11) ALL. MLL-Af4 DNA binding drives differential gene expression distinct from MLL-AF9 and confers cells with a lymphoid preference.


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