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Role of the transcription factor E47 in uncommitted hematopoietic progenitors
Author(s) -
Borghesi Lisa,
Yang Qi,
Aites Jennifer
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.844.2
Subject(s) - haematopoiesis , progenitor cell , transcription factor , microbiology and biotechnology , biology , recombinase , cre recombinase , stem cell , genetics , gene , transgene , recombination , genetically modified mouse
Uncommitted bone marrow precursors replenish the immune system throughout life, and it is of great interest to understand the mechanisms that control their functional integrity. We show that E47 knockout (KO) mice have major defects in multipotent LSKs, a subset that contains self‐renewing hematopoietic progenitors. We have found that LSKs from E47 KO mice have skewed levels of the flk2/flt3 cytokine receptor as well as the cell cycle regulator p21. 70% of wild type LSKs are flk2+ versus only 30% of E47 KO LSKs. Moreover, p21 expression is reduced by 50% in the latter mice. Two populations thought to be downstream of LSKs, common lymphoid progenitors (CLPs) and early thymic progenitors (ETPs) are both reduced ~4–10‐fold in E47 KO animals. While V(D)J recombinase activity, an indicator of lymphoid lineage progression, is normally expressed in ~50% of CLPs and ETPs, interruption of E47 impairs this process. We have shown that loss of E47 ablates recombinase activity in CLPs and now show that loss of E47:HEB complexes ablates recombinase activity in ETPs. Specifically, inhibition of E47:HEB leads to a 40% reduction in recombination activity as assessed at the single cell level. Together, these data indicate a key role for E47 in the functional integrity of LSKs, and the ability of these cells to effectively repopulate downstream lymphoid compartments. Support from: NIH, Elsa U Pardee Cancer Research Foundation, and USIDNET.