Cell fate decisions in malignant hematopoiesis: leukemia phenotype is determined by distinct functional domains of the MN1 oncogene

Courteney K Lai; Yeonsook Moon; Florian Kuchenbauer; Daniel T Starzcynowski; Bob Argiropoulos; Eric Yung; Philip Beer; Adrian Schwarzer; Amit Sharma; Gyeongsin Park; Malina Leung; Grace Lin; Sarah Vollett; Stephen Fung; Connie J Eaves; Aly Karsan; Andrew P Weng; R Keith Humphries; Michael Heuser

doi:10.1371/journal.pone.0112671

Cell fate decisions in malignant hematopoiesis: leukemia phenotype is determined by distinct functional domains of the MN1 oncogene

PLoS One. 2014 Nov 17;9(11):e112671. doi: 10.1371/journal.pone.0112671. eCollection 2014.

Authors

Courteney K Lai¹, Yeonsook Moon², Florian Kuchenbauer³, Daniel T Starzcynowski⁴, Bob Argiropoulos⁵, Eric Yung⁶, Philip Beer⁶, Adrian Schwarzer⁷, Amit Sharma⁷, Gyeongsin Park⁸, Malina Leung⁶, Grace Lin⁶, Sarah Vollett⁶, Stephen Fung⁶, Connie J Eaves¹, Aly Karsan⁹, Andrew P Weng¹⁰, R Keith Humphries¹, Michael Heuser¹¹

Affiliations

¹ Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada; Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
² Department of Laboratory Medicine, Medical School of Inha University, Incheon, Korea.
³ Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany; Institute of Experimental Cancer Research, Comprehensive Cancer Centre, University Hospital of Ulm, Ulm, Germany.
⁴ Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
⁵ Department of Medical Genetics, University of Calgary, Calgary, AB, Canada.
⁶ Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada.
⁷ Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
⁸ Department of Hospital Pathology, Catholic University of Korea, Seoul, Korea.
⁹ Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁰ Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹¹ Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

Abstract

Extensive molecular profiling of leukemias and preleukemic diseases has revealed that distinct clinical entities, like acute myeloid (AML) and T-lymphoblastic leukemia (T-ALL), share similar pathogenetic mutations. It is not well understood how the cell of origin, accompanying mutations, extracellular signals or structural differences in a mutated gene determine the phenotypic identity of leukemias. We dissected the functional aspects of different protein regions of the MN1 oncogene and their effect on the leukemic phenotype, building on the ability of MN1 to induce leukemia without accompanying mutations. We found that the most C-terminal region of MN1 was required to block myeloid differentiation at an early stage, and deletion of an extended C-terminal region resulted in loss of myeloid identity and cell differentiation along the T-cell lineage in vivo. Megakaryocytic/erythroid lineage differentiation was blocked by the N-terminal region. In addition, the N-terminus was required for proliferation and leukemogenesis in vitro and in vivo through upregulation of HoxA9, HoxA10 and Meis2. Our results provide evidence that a single oncogene can modulate cellular identity of leukemic cells based on its active gene regions. It is therefore likely that different mutations in the same oncogene may impact cell fate decisions and phenotypic appearance of malignant diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow Cells / metabolism
Bone Marrow Cells / pathology
Cell Differentiation / genetics
Cell Transformation, Neoplastic / genetics
Cluster Analysis
Gene Expression Profiling
Hematopoiesis / genetics*
Humans
Leukemia / genetics*
Leukemia / metabolism
Leukemia / pathology*
Megakaryocyte-Erythroid Progenitor Cells / metabolism
Megakaryocyte-Erythroid Progenitor Cells / pathology
Mice
Mutation
Myeloid Cells / metabolism
Myeloid Cells / pathology
Phenotype*
Protein Interaction Domains and Motifs / genetics
T-Lymphocytes / metabolism
T-Lymphocytes / pathology
Trans-Activators
Tumor Suppressor Proteins / chemistry
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism

Substances

MN1 protein, human
Trans-Activators
Tumor Suppressor Proteins

Associated data

GEO/GSE46990

Grants and funding

This study was supported by grants from the Terry Fox Foundation, Canada (http://www.terryfox.org/TerryFox/The_Terry_Fox_Foundation.html) (grant Nos. 18006 and 122869), the Cancer Research Society, Canada (http://www.crs-src.ca/), the Stem Cell Network of Canada (http://www.stemcellnetwork.ca/index.php?page=funding-opportunities), Deutsche Krebshilfe e.V (grant No. 109003, 110284, 110292, and 111267) (http://www.krebshilfe.de/metanavigation/english.html), grant No. DJCLS H09/1f, R 10/22, and R13/14 from the Deutsche-José-Carreras Leukämie-Stiftung e.V (http://www.carreras-stiftung.de/); grant No. M 47.1 from the H. W. & J. Hector Stiftung (http://www.hector-stiftung.de/), the German Federal Ministry of Education and Research grant 01EO0802 (IFB-Tx) (http://www.bmbf.de/en/14580.php), and DFG grants HE 5240/4-1, HE 5240/5-1 (http://www.dfg.de/en/research_funding/programmes/individual/research_grants/). CKL was supported by studentships from the Canadian Institute of Health Research (http://www.cihr-irsc.gc.ca/e/193.html#), the University of British Columbia (https://www.grad.ubc.ca/awards/four-year-doctoral-fellowship-4yf), and the BC Cancer Agency (http://www.bccancer.bc.ca/default.htm). FK was supported by grants from Deutsche Krebshilfe grant 109420 (Max-Eder program) (http://www.krebshilfe.de/metanavigation/english.html); fellowship 2010/04 by the European Hematology Association (http://www.ehaweb.org/career/career-development-grants/eha-research-fellowships-and-the-jose-carreras-foundation-eha-young-investigator-fellowship/); and by the Deutsche Forschungsgemeinschaft (grant D.3955 (SFB 1074)) (http://www.dfg.de/en/research_funding/programmes/individual/). PB was supported by an intermediate fellowship from the Kay Kendall Leukaemia Fund (http://www.kklf.org.uk/intermediate.html). GL was supported by a BC Cancer Studentship from the BC Cancer Agency (http://www.bccancer.bc.ca/default.htm). SV was supported by a studentship from the Stem Cell Network of Canada (http://www.stemcellnetwork.ca/index.php?page=co-op-award). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.