These Spi1tm1.3Dgt knock-out mice develop T cell lymphoma and acute myeloid lymphoma.
Daniel G. Tenen, Beth Israel Deaconess Medical Center
Mice homozygous for this targeted deletion are viable and fertile as young animals. Mice on this stock (predominantly 129Sv) background often die between 3-8 months of age of a rapidly developing T cell lymphoma (64% penetrance) or between 6-12 months of acute myeloid lymphoma (AML) (29% penetrance). Homozygotes (termed PU.1 knockdown or UREdelta) have an 80% reduction of endogeneous gene expression. This is associated with an accumulation of hematopoietic stem cell precursor cells and neutrophils in bone marrow and spleen. Bone marrow cells from homozygous mice have abnormal responses to myeloid cytokines, and malignant transformation is associated with clonal chromosomal abnormalities. Homozygous mice have abnormal B- and T-cell populations and lineage commitment. These mice may be useful in studying T cell lymphoma, AML and other cancers, transcription factors, and development of multiple cell lineages.
Of note, the latency and penetrance of disease is slightly different from those homozygous mice harboring the URE deletion (and neo cassette) on a mixed BALB/c, C57BL/6, and 129 background (see Sfpi1tm1.1 mice described in Rosenbauer 2004 Nat Genet 36:624).
A targeting vector was designed to place a loxP site on both sides of the 3.4 kb upstream regulatory element (URE) located 14 kb upstream of the endogenous gene. This also inserted a FRT-flanked PGKneo cassette immediately upstream of the loxP-flanked genome. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Chimeric mice were interbred or crossed to C57BL/6 females, resulting in mutant -14kb UREloxP+neo (or Sfpi1tm1Dgt) mice. These were next crossed with BALB/c mice carrying the CMV-cre transgene to excise the URE, creating UREdelta-neo (also called deltaURE-neo, Sfpi1tm1.1). The neomycin resistance cassette was next removed by breeding heterozygous UREdelta-neo mutants on a mixed (but predominantly BALB/c) background with 129Sv mice carrying a "ROSA-FLP" transgene. The resulting offspring (on a mixed, but predominantly 129Sv, background) with the endogenous -14kb upstream regulatory element now replaced with a single FRT and loxP site were maintained by breeding heterozygotes prior to arrival at The Jackson Laboratory.
|Allele Name||targeted mutation 1.3, Daniel G Tenen|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||PU.1 knockdown; UREdelta; UREdelta (neo-)|
|Gene Symbol and Name||Spi1, spleen focus forming virus (SFFV) proviral integration oncogene|
|Gene Synonym(s)||Dis-1; OF; PU.1; Pu.1; SFFV proviral integration 1; SFPI1; SPI-1; SPI-A; Sfpi-1; Sfpi-1; Sfpi1; Sfpi1; Spi-1; Tcfpu1; Tcfpu1; Tfpu.1; Tfpu.1; transcription factor PU.1|
|Strain of Origin||(129X1/SvJ x 129S1/Sv)F1-Kitl<+>|
|General Note||Although expression of PU.1/SFPI1 in hematopoietic stem cells, myeloid progenitor cells and granulocytes is similar in mice homozygous for this mutation and for Sfpi1tm1.1Dgt ("UREdeltaneo"), which retains the PGK-neo cassette, mice with the present mutation develop acute myelocytic leukemia (AML) with a lower penetrance (29% vs. 97%) and a longer latency (6-12 months vs. 3-8 months) than do those with Sfpi1tm1.1Dgt. Mice with the present mutation often die of T cell lymphoma before the time of onset of AML. (J:106789;J:90331) The phenotypic difference may be due to genetic background differences, as Sfpi1tm1.1Dgt was analyzed on a ~50% BALB/c and the present mutation on a greater than 50% 129/Sv background.|
|Molecular Note||This allele was generated from Sfpi1tm1Dgt by sequential deletion of the loxP-flanked 3.4-kb upstream regulatory element (URE), located 14 kb upstream from the endogenous gene, and of the FRT-flanked PGK-Neo cassette residing immediately upstream of the URE, achieved by crossing mice bearing the Sfpi1 mutations with animals ubiquitously expressing Cre and FLP recombinase, respectively. Thus it lacks both the normal URE and the introduced PGK-neo cassette, with single loxP and FRT sites markingtheir former locations. Expression of the gene in bone marrow and purified hematopoietic stem cells (HSCs) of homozygous mutant mice is reduced to ~80% of wild-type levels.|
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