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 Assi; Mark  Wunderlich; Toshihiko  Lmamura; Joseph J.  Kaberlein; Ahmad  Rayes; Mark J.  Althoff; John  Anastasi; Maureen M.  O’Brien; Amom Ruhikanta Meetei; Thomas A. Milne; Constanze Bonifer; James 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 Assi
, Mark Wunderlich
, Toshihiko Lmamura
, Joseph J. Kaberlein
, Ahmad Rayes
, Mark J. Althoff
, John Anastasi
, Maureen M. O’Brien
, Amom Ruhikanta Meetei
, Thomas A. Milne
, Constanze Bonifer
, James Mulloy
, Michael J. Thirman

Cancer and Genomic Sciences

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

52 Citations (Scopus)

311 Downloads (Pure)

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
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
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

UN SDGs

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

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10.1016/j.ccell.2016.10.008

Cancer cell MLL-AF4Accepted author manuscript, 6.66 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

https://www.sciencedirect.com/science/article/pii/S1535610816304950Licence: None: All rights reserved

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Lin, S., Luo, R. T., Ptasinska, A., Kerry, J., Assi, S., Wunderlich, M., Lmamura, 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., & 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

@article{93368e3c935e4734b4c7aed32c607068,

title = "Instructive role of MLL-fusion proteins revealed by a model of t(4;11) pro-B acute lymphoblastic leukemia",

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. ",

keywords = "MLL-AF4, acute lymphoblastic leukemi, chimeric fusion proteins, mouse models of cancer, acquired resistance to targeted therapy, species specificity of oncogenes",

author = "Shan Lin and Luo, \{Roger T.\} and Anetta Ptasinska and Jon Kerry and Salam Assi and Mark Wunderlich and Toshihiko Lmamura and Kaberlein, \{Joseph J.\} and Ahmad Rayes and Althoff, \{Mark J.\} and John Anastasi and O{\textquoteright}Brien, \{Maureen M.\} and Meetei, \{Amom Ruhikanta\} and Milne, \{Thomas A.\} and Constanze Bonifer and James Mulloy and Thirman, \{Michael J.\}",

year = "2016",

month = nov,

day = "14",

doi = "10.1016/j.ccell.2016.10.008",

language = "English",

volume = "30",

pages = "737–749",

journal = "Cancer Cell",

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Lin, S, Luo, RT, Ptasinska, A, Kerry, J, Assi, S, Wunderlich, M, Lmamura, T, Kaberlein, JJ, Rayes, A, Althoff, MJ, Anastasi, J, O’Brien, MM, Meetei, AR, Milne, TA, Bonifer, C, Mulloy, J & 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

TY - JOUR

T1 - Instructive role of MLL-fusion proteins revealed by a model of t(4;11) pro-B acute lymphoblastic leukemia

AU - Lin, Shan

AU - Luo, Roger T.

AU - Ptasinska, Anetta

AU - Kerry, Jon

AU - Assi, Salam

AU - Wunderlich, Mark

AU - Lmamura, Toshihiko

AU - Kaberlein, Joseph J.

AU - Rayes, Ahmad

AU - Althoff, Mark J.

AU - Anastasi, John

AU - O’Brien, Maureen M.

AU - Meetei, Amom Ruhikanta

AU - Milne, Thomas A.

AU - Bonifer, Constanze

AU - Mulloy, James

AU - Thirman, Michael J.

PY - 2016/11/14

Y1 - 2016/11/14

N2 - 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.

AB - 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.

KW - MLL-AF4

KW - acute lymphoblastic leukemi

KW - chimeric fusion proteins

KW - mouse models of cancer

KW - acquired resistance to targeted therapy

KW - species specificity of oncogenes

U2 - 10.1016/j.ccell.2016.10.008

DO - 10.1016/j.ccell.2016.10.008

M3 - Article

SN - 1535-6108

VL - 30

SP - 737

EP - 749

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

Instructive role of MLL-fusion proteins revealed by a model of t(4;11) pro-B acute lymphoblastic leukemia

Abstract

Keywords

UN SDGs

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