Plzf drives MLL-fusion–mediated leukemogenesis specifically in long-term hematopoietic stem cells

Autor: Naoyuki Katayama, Kei Suzuki, Masahiro Masuya, Satomi Ishii, Tetsuya Nosaka, Hideaki Nakajima, Akihide Nakamura, Fumi Shibata-Minoshima, Yutaka Enomoto, Ryoichi Ono, Toshio Kitamura, Eri Miyata
Rok vydání: 2013
Předmět:
Acute promyelocytic leukemia
Oncogene Proteins
Fusion
Cellular differentiation
Blotting
Western
Immunology
Kruppel-Like Transcription Factors
Mice
Transgenic
Biology
Real-Time Polymerase Chain Reaction
Biochemistry
Fusion gene
Mice
hemic and lymphatic diseases
Biomarkers
Tumor
medicine
Animals
Humans
Promyelocytic Leukemia Zinc Finger Protein
RNA
Messenger
Myeloid Progenitor Cells
Cell Proliferation
Oligonucleotide Array Sequence Analysis
Leukemia
Reverse Transcriptase Polymerase Chain Reaction
Gene Expression Profiling
Myeloid leukemia
Cell Differentiation
Cell Biology
Hematology
Flow Cytometry
Hematopoietic Stem Cells
medicine.disease
Virology
Fusion protein
Cell biology
Mice
Inbred C57BL
Haematopoiesis
Cell Transformation
Neoplastic
Retroviridae
Stem cell
Myeloid-Lymphoid Leukemia Protein
Zdroj: Blood. 122:1271-1283
ISSN: 1528-0020
0006-4971
Popis: Oncogenic transformation requires unlimited self-renewal. Currently, it remains unclear whether a normal capacity for self-renewal is required for acquiring an aberrant self-renewal capacity. Our results in a new conditional transgenic mouse showed that a mixed lineage leukemia (MLL) fusion oncogene, MLL-ENL, at an endogenous-like expression level led to leukemic transformation selectively in a restricted subpopulation of hematopoietic stem cells (HSCs) through upregulation of promyelocytic leukemia zinc finger (Plzf). Interestingly, forced expression of Plzf itself immortalized HSCs and myeloid progenitors in vitro without upregulation of Hoxa9/Meis1, which are well-known targets of MLL fusion proteins, whereas its mutant lacking the BTB/POZ domain did not. In contrast, depletion of Plzf suppressed the MLL-fusion-induced leukemic transformation of HSCs in vitro and in vivo. Gene expression analyses of human clinical samples showed that a subtype of PLZF-high MLL-rearranged myeloid leukemia cells was closely associated with the gene expression signature of HSCs. These findings suggested that MLL fusion protein enhances the self-renewal potential of normal HSCs to develop leukemia, in part through a Plzf-driven self-renewal program.
Databáze: OpenAIRE
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