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

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

doi:10.1016/j.ccell.2016.10.008

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

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

Research output: Contribution to journal › Article › peer-review

109 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	737-749
Number of pages	13
Journal	Cancer Cell
Volume	30
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2016.10.008
State	Published - Nov 14 2016
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

MLL-AF4
acquired resistance to targeted therapy
acute lymphoblastic leukemia
chimeric fusion proteins
mouse models of cancer
species specificity of oncogenes

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10.1016/j.ccell.2016.10.008

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Lin, S., Luo, R. T., Ptasinska, A., Kerry, J., Assi, S. A., Wunderlich, M., Imamura, T., Kaberlein, J. J., Rayes, A., Althoff, M. J., Anastasi, J., O'Brien, M. M., Meetei, A. R., Milne, T. A., Bonifer, C., Mulloy, J. C., & Thirman, M. J. (2016). Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia. Cancer Cell, 30(5), 737-749. https://doi.org/10.1016/j.ccell.2016.10.008

Lin, S, Luo, RT, Ptasinska, A, Kerry, J, Assi, SA, Wunderlich, M, Imamura, T, Kaberlein, JJ, Rayes, A, Althoff, MJ, Anastasi, J, O'Brien, MM, Meetei, AR, Milne, TA, Bonifer, C, Mulloy, JC & Thirman, MJ 2016, 'Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia', Cancer Cell, vol. 30, no. 5, pp. 737-749. https://doi.org/10.1016/j.ccell.2016.10.008

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abstract = "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.",

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AB - 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.

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KW - chimeric fusion proteins

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KW - species specificity of oncogenes

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

Abstract

Bibliographical note

UN SDGs

Keywords

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