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

82 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

Funding Information:
We thank G. Huang, A. Kumar, M. Azam, J. Vardiman and members of the Mulloy and Thirman laboratories for reagents, experimental assistance and feedback. This work was supported by an Institutional Clinical and Translational Science Award, NIH/NCRR Grant Number 1UL1RR026314-01, Translational Trials Development and Support Laboratory award (U.S.P.H.S. Grant number MO1 RR 08084), a Center of Excellence in Molecular Hematology P30 award (DK090971), a CancerFree KIDS Research Award (to S.L.), an American Society of Hematology Bridge grant (to M.J.T.), the Jerome Thrall Memorial Fund (to M.J.T.), a Leukemia and Lymphoma Society Translational Research Grant (to M.J.T.), the FH Paschen Fund (to M.J.T.), a Leukemia and Lymphoma Society Scholar award (to J.C.M.), grants from Bloodwise and the Kay Kendall Leukemia Fund (to C.B.), the assistance of the CCHMC Research Flow Cytometry Core, CCHMC Translational Core Laboratory, CCHMC Pathology Core and CCHMC Comprehensive Mouse and Cancer Core, Genomics, Epigenomics and Sequencing Core (NIEHS P30-ES006096), the sequencing facility of the University of Birmingham (UK) and Statistical Genomics and Systems Biology Core at the University of Cincinnati, and the Genomics Core and the Cytometry and Antibody Technology Core of the University of Chicago. TAM and JK are supported by a Medical Research Council (MRC, UK) Molecular Haematology Unit grant MC_UU_12009/6. T.A.M. is one of the founding shareholders of Oxstem Oncology (OSO), a subsidiary company of OxStem Ltd (2016).

Publisher Copyright:
© 2016 Elsevier Inc.

Keywords

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

UN SDGs

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

Publisher link

10.1016/j.ccell.2016.10.008

Find It

Find It at U of M Libraries

Cite this

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

@article{799adbc2ceaf4c3abf00abafd2028d9f,

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 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.",

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

author = "Shan Lin and Luo, {Roger T.} and Anetta Ptasinska and Jon Kerry and Assi, {Salam A.} and Mark Wunderlich and Toshihiko Imamura and Kaberlein, {Joseph J.} and Ahmad Rayes and Althoff, {Mark J.} and John Anastasi and O'Brien, {Maureen M.} and Meetei, {Amom Ruhikanta} and Milne, {Thomas A.} and Constanze Bonifer and Mulloy, {James C.} and Thirman, {Michael J.}",

note = "Funding Information: We thank G. Huang, A. Kumar, M. Azam, J. Vardiman and members of the Mulloy and Thirman laboratories for reagents, experimental assistance and feedback. This work was supported by an Institutional Clinical and Translational Science Award, NIH/NCRR Grant Number 1UL1RR026314-01, Translational Trials Development and Support Laboratory award (U.S.P.H.S. Grant number MO1 RR 08084), a Center of Excellence in Molecular Hematology P30 award (DK090971), a CancerFree KIDS Research Award (to S.L.), an American Society of Hematology Bridge grant (to M.J.T.), the Jerome Thrall Memorial Fund (to M.J.T.), a Leukemia and Lymphoma Society Translational Research Grant (to M.J.T.), the FH Paschen Fund (to M.J.T.), a Leukemia and Lymphoma Society Scholar award (to J.C.M.), grants from Bloodwise and the Kay Kendall Leukemia Fund (to C.B.), the assistance of the CCHMC Research Flow Cytometry Core, CCHMC Translational Core Laboratory, CCHMC Pathology Core and CCHMC Comprehensive Mouse and Cancer Core, Genomics, Epigenomics and Sequencing Core (NIEHS P30-ES006096), the sequencing facility of the University of Birmingham (UK) and Statistical Genomics and Systems Biology Core at the University of Cincinnati, and the Genomics Core and the Cytometry and Antibody Technology Core of the University of Chicago. TAM and JK are supported by a Medical Research Council (MRC, UK) Molecular Haematology Unit grant MC_UU_12009/6. T.A.M. is one of the founding shareholders of Oxstem Oncology (OSO), a subsidiary company of OxStem Ltd (2016). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = nov,

day = "14",

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

language = "English (US)",

volume = "30",

pages = "737--749",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

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 A.

AU - Wunderlich, Mark

AU - Imamura, 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 C.

AU - Thirman, Michael J.

N1 - Funding Information: We thank G. Huang, A. Kumar, M. Azam, J. Vardiman and members of the Mulloy and Thirman laboratories for reagents, experimental assistance and feedback. This work was supported by an Institutional Clinical and Translational Science Award, NIH/NCRR Grant Number 1UL1RR026314-01, Translational Trials Development and Support Laboratory award (U.S.P.H.S. Grant number MO1 RR 08084), a Center of Excellence in Molecular Hematology P30 award (DK090971), a CancerFree KIDS Research Award (to S.L.), an American Society of Hematology Bridge grant (to M.J.T.), the Jerome Thrall Memorial Fund (to M.J.T.), a Leukemia and Lymphoma Society Translational Research Grant (to M.J.T.), the FH Paschen Fund (to M.J.T.), a Leukemia and Lymphoma Society Scholar award (to J.C.M.), grants from Bloodwise and the Kay Kendall Leukemia Fund (to C.B.), the assistance of the CCHMC Research Flow Cytometry Core, CCHMC Translational Core Laboratory, CCHMC Pathology Core and CCHMC Comprehensive Mouse and Cancer Core, Genomics, Epigenomics and Sequencing Core (NIEHS P30-ES006096), the sequencing facility of the University of Birmingham (UK) and Statistical Genomics and Systems Biology Core at the University of Cincinnati, and the Genomics Core and the Cytometry and Antibody Technology Core of the University of Chicago. TAM and JK are supported by a Medical Research Council (MRC, UK) Molecular Haematology Unit grant MC_UU_12009/6. T.A.M. is one of the founding shareholders of Oxstem Oncology (OSO), a subsidiary company of OxStem Ltd (2016). Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/11/14

Y1 - 2016/11/14

N2 - 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.

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.

KW - MLL-AF4

KW - acquired resistance to targeted therapy

KW - acute lymphoblastic leukemia

KW - chimeric fusion proteins

KW - mouse models of cancer

KW - species specificity of oncogenes

UR - http://www.scopus.com/inward/record.url?scp=85006493398&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006493398&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2016.10.008

DO - 10.1016/j.ccell.2016.10.008

M3 - Article

C2 - 27846391

AN - SCOPUS:85006493398

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

Bibliographical note

Keywords

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this