Cell fate decisions in malignant hematopoiesis: leukemia phenotype is determined by distinct functional domains of the MN1 oncogene.
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.
Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada; Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
Courteney K
CK
Lai
Department of Laboratory Medicine, Medical School of Inha University, Incheon, Korea.
Yeonsook
Y
Moon
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.
Florian
F
Kuchenbauer
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Daniel T
DT
Starzcynowski
Department of Medical Genetics, University of Calgary, Calgary, AB, Canada.
Bob
B
Argiropoulos
Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada.
Eric
E
Yung
Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada.
Philip
P
Beer
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
Adrian
A
Schwarzer
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
Amit
A
Sharma
Department of Hospital Pathology, Catholic University of Korea, Seoul, Korea.
Gyeongsin
G
Park
Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada.
Malina
M
Leung
Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada.
Grace
G
Lin
Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada.
Sarah
S
Vollett
Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada.
Stephen
S
Fung
Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada; Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
Connie J
CJ
Eaves
Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Aly
A
Karsan
Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Andrew P
AP
Weng
Terry Fox Laboratory, BC Cancer Agency Research Centre, Vancouver, BC, Canada; Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
R Keith
RK
Humphries
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Michael
M
Heuser
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D055015:Megakaryocyte-Erythroid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
C506524:MN1 protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins