Open AccessDose-dependent repression of T-cell and natural killer cell genes by PU.1 enforces myeloid and B-cell identity
Author(s) -
Meghana B. Kamath,
Isaac B. Houston,
Alexander Janovski,
Xiang Yang Zhu,
Sivakumar Gowrisankar,
Anil G. Jegga,
Rodney P. DeKoter
Publication year - 2008
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/leu.2008.67
Subject(s) - myeloid , biology , haematopoiesis , progenitor cell , b cell , cell , natural killer cell , stem cell , microbiology and biotechnology , ex vivo , lymphopoiesis , cell growth , cancer research , immunology , in vivo , genetics , in vitro , cytotoxic t cell , antibody
The Ets transcription factor PU.1, encoded by the gene Sfpi1, functions in a concentration-dependent manner to promote myeloid and B-cell development and has been implicated in myeloid and lymphoid leukemias. To determine the consequences of reducing PU.1 concentration during hematopoiesis, we analyzed mice with two distinct hypomorphic alleles of Sfpi1 that produce PU.1 at approximately 20% (BN) or approximately 2% (Blac) of wild-type levels. Myeloid development was impaired in these mice, but less severely than in Sfpi1 null mice. To identify the downstream target genes that respond to changes in PU.1 concentration, we analyzed ex vivo interleukin-3 dependent myeloid cell lines established from Sfpi1(BN/BN), Sfpi1(Blac/Blac) and Sfpi1(-/-) fetal liver cells. Unexpectedly, many T-cell and natural killer cell genes were expressed in Sfpi1(-/-) cells and repressed in a dose-dependent manner in Sfpi1(Blac/Blac) and Sfpi1(BN/BN) cells. This pattern of dose-dependent T/NK-cell gene repression also occurred in ex vivo interleukin-7 dependent progenitor B cell lines. These results suggest that PU.1 functions in a concentration-dependent manner to repress T-cell and natural killer cell fates while promoting myeloid and B-cell fates.