EWSR1/ELF5 induces acute myeloid leukemia by inhibiting p53/p21 pathway

Akifumi Endo; Daisuke Tomizawa; Yuki Aoki; Tomohiro Morio; Shuki Mizutani; Masatoshi Takagi

doi:10.1111/cas.13080

EWSR1/ELF5 induces acute myeloid leukemia by inhibiting p53/p21 pathway

Cancer Sci. 2016 Dec;107(12):1745-1754. doi: 10.1111/cas.13080. Epub 2016 Nov 25.

Authors

Akifumi Endo¹, Daisuke Tomizawa^{1

2}, Yuki Aoki^{1

3}, Tomohiro Morio¹, Shuki Mizutani¹, Masatoshi Takagi¹

Affiliations

¹ Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
² Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
³ Department of Pediatric Oncology, National Cancer Center, Tokyo, Japan.

Abstract

The Ewing sarcoma breakpoint region 1 (EWSR1) gene is known to fuse with various partner genes to promote the development of the Ewing sarcoma family of tumors and other sarcomas. In contrast, the association of EWSR1 chimeric fusion genes with leukemia has rarely been reported. We identified a novel EWSR1-associated chimeric fusion gene in a patient with acute myeloid leukemia harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality. The patient was refractory to intensified chemotherapy including hematopoietic stem cell transplantation. Total RNA paired-end sequencing identified a novel chimeric fusion gene as EWSR1/ELF5, a member of the E26 transformation-specific transcription factor family. Transduction of EWSR1/ELF5 to NIH3T3 cells induced transformation by attenuating with the p53/p21-dependent pathway. The injection of EWSR1/ELF5-transduced NIH3T3 cells into NSG-SCID mice systematically induced the development of tumors in vivo. These results revealed the oncogenic potency of EWSR1/ELF5.

Keywords: Acute myelogenous leukemia; ELF5; EWSR1; TP53; senescence.

MeSH terms

Animals
Calmodulin-Binding Proteins / genetics*
Cell Line, Transformed
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Child, Preschool
Chromosome Banding
DNA-Binding Proteins
Disease Models, Animal
Female
Gene Expression
Gene Expression Profiling
Humans
In Situ Hybridization, Fluorescence
Leukemia, Myeloid, Acute / diagnosis
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism*
Male
Mice
Mutation
NIH 3T3 Cells
Oncogene Proteins, Fusion / genetics*
Oncogene Proteins, Fusion / metabolism
Proto-Oncogene Proteins c-ets / genetics*
Proto-Oncogene Proteins p21(ras) / agonists
Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
Proto-Oncogene Proteins p21(ras) / metabolism*
RNA-Binding Protein EWS
RNA-Binding Proteins / genetics*
Signal Transduction*
Transcription Factors
Transcriptome
Tumor Suppressor Protein p53 / metabolism*

Substances

Calmodulin-Binding Proteins
DNA-Binding Proteins
ELF5 protein, human
EWSR1 protein, human
Oncogene Proteins, Fusion
Proto-Oncogene Proteins c-ets
RNA-Binding Protein EWS
RNA-Binding Proteins
Transcription Factors
Tumor Suppressor Protein p53
Proto-Oncogene Proteins p21(ras)