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

Ryoichi Ono, Masahiro Masuya, Hideaki Nakajima, Yutaka Enomoto, Eri Miyata, Akihide Nakamura, Satomi Ishii, Kei Suzuki, Fumi Shibata-Minoshima, Naoyuki Katayama, Toshio Kitamura, Tetsuya Nosaka

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1271-1283
Number of pages13
JournalBlood
Volume122
Issue number7
DOIs
Publication statusPublished - 2013 Aug 15
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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  • Cite this

    Ono, R., Masuya, M., Nakajima, H., Enomoto, Y., Miyata, E., Nakamura, A., Ishii, S., Suzuki, K., Shibata-Minoshima, F., Katayama, N., Kitamura, T., & Nosaka, T. (2013). Plzf drives MLL-fusion-mediated leukemogenesis specifically in long-term hematopoietic stem cells. Blood, 122(7), 1271-1283. https://doi.org/10.1182/blood-2012-09-456665