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 journalArticlepeer-review

48 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 languageEnglish (US)
Pages (from-to)737-749
Number of pages13
JournalCancer Cell
Volume30
Issue number5
DOIs
StatePublished - Nov 14 2016

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).

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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