The down regulation of Sfpi1/PU.1 has also been reported in human AML cases revealing one common pathway of myeloid disruption between mouse and human AML where dysregulation of Sfpi1/PU.1 is a necessary step in AML development.
Overall, our results reveal senescence as a Spi1-induced anti-proliferative mechanism that may be a safeguard against the development of acute myeloid leukemia.
These results table the SPI1-GFI1B transcriptional network as an important regulatory axis in AML as well as in the development of erythroid versus myelomonocytic cell fate.
Consistent with murine data, heterozygous deletion of the SPI1 locus and mutation of the -14kb SPI1 upstream regulatory element were described previously in human primary AML, although they are rare events.
Since the involvement of stem cells is considered to be important in hematological malignancies as well as normal hematopoiesis, we examined the expression of newly defined HSC factors including HOXB4, TCFEC, HMGB-1, FOS, and SPI-1 in the bone marrow (BM) from de novo acute myeloid leukemia (AML) patients.
Our results establish a novel cooperation between Sox4 and reduced Sfpi1 expression in myeloid leukemia development and suggest that SOX4 could be an important new therapeutic target in human acute myeloid leukemia.
We found that mice carrying hypomorphic Sfpi1 alleles that reduce PU.1 expression to 20% of normal levels, unlike mice carrying homo- or heterozygous deletions of Sfpi1, developed AML.
We found that mice carrying hypomorphic Sfpi1 alleles that reduce PU.1 expression to 20% of normal levels, unlike mice carrying homo- or heterozygous deletions of Sfpi1, developed AML.
YAC contig construction, together with data suggesting that the critical gene flanks Sfpi1, represents significant progress toward identifying an AML tumor suppressor gene.