Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Cell Differentiation
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology*
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Flow Cytometry
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Gene Expression Profiling
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / pathology*
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Humans
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Kruppel-Like Transcription Factors / antagonists & inhibitors
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism*
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Leukemia / etiology*
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Leukemia / metabolism
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Leukemia / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Myeloid Progenitor Cells / metabolism
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Myeloid Progenitor Cells / pathology*
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Myeloid-Lymphoid Leukemia Protein / genetics*
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Oligonucleotide Array Sequence Analysis
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Oncogene Proteins, Fusion / genetics*
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Promyelocytic Leukemia Zinc Finger Protein
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Retroviridae / genetics
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Reverse Transcriptase Polymerase Chain Reaction
Substances
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Biomarkers, Tumor
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Kruppel-Like Transcription Factors
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MLL-ENL oncoprotein, human
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Oncogene Proteins, Fusion
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Promyelocytic Leukemia Zinc Finger Protein
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RNA, Messenger
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Zbtb16 protein, mouse
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Myeloid-Lymphoid Leukemia Protein