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 |
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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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