All Phenotypes Spi1<tm1.3Dgt> MGI Mouse

Mouse Models of Human Disease	DO ID	OMIM ID(s)	Ref(s)
acute myeloid leukemia	DOID:9119	OMIM:601626	J:90331

premature death ( J:106040 )

• > 90% of mice homozygous for this mutation die between 3 and 13 months of age

increased T cell derived lymphoma incidence ( J:106040 )

• in 40% of mice with thymic lymphoma, lymphoma cells are present in the periphery where they greatly elevate peripheral blood lymphocyte numbers, form spleen and/or lymph node tumors, and invade nonhematopoietic organs

• T-cell lymphoma cells of homozygous mutant mice vary in their expression of CD4 and CD8 and are CD3^dim

• lymphoma cells of mutant mice express terminal deoxynucleotide transferase, a characteristic of immature T lymphoblast cells

• the lymphoma cells, unlike ordinary T-cell progenitor cells in these mice, express only low levels of PU.1/SFPI1

• analysis of the TCR-beta variable-region isotype of T-cell lymphoma cells from lymph node tumors indicates they are clonally derived

• a characteristic pattern of promoter hypermethylation is detected by RLGS analysis in T-cell lymphomas (but not in myeloid tumors) of homozygous mutant mice

• hypermethylation and transcriptional downregulation of the inhibitor of DNA binding 4 (Id4) tumor suppressor gene is characteristic of T-cell lymphomas, but not of myeloid tumors, of homozygous mutant mice

• T-cell lymphomas of these mice exhibit a characteristic pattern of promoter hypermethylation that is not shared by myeloid tumors in the same mice; inhibitor of DNA binding 4 (Id4, aka Idb4) is reproducibly hypermethylated and downregulated in these but not AML

• injection of lymphoma cells transmits the phenoytpe to NOD.CB17-Prkdc^scid mice, causing death within 3-6 weeks

increased leukemia incidence ( J:106040 )

• between 6 and 12 months of age, 29.0% of homozygous mice develop acute myeloid leukemia (AML)

small thymus ( J:106040 )

decreased pro-B cell number ( J:106040 )

• numbers of bone marrow pro-B cells (Lin^-IgM^-B220⁺CD43⁺) are greatly reduced

arrested B cell differentiation ( J:106040 )

• B cell differentiation is blocked before the pro-B cell stage in mutant mice, as numbers of bone marrow pro-B cells (Lin^-IgM^-B220⁺CD43⁺) and pre-B cells (Lin^-IgM^-B220⁺CD43^-) are greatly reduced

abnormal double-negative T cell morphology ( J:106040 )

• SFPI1/PU.1 is expressed at higher levels in mutant than in wild-type ETPs and DN1-DN3 thymocytes, but is turned off in both mutant and wild-type CD4⁺CD8⁺ (double positive, DP) thymocytes

decreased granulocyte number ( J:106040 )

• proportion of myeloid cells (Mac1^lowIgm^-) in the peritoneum diminishes over time

decreased mature B cell number ( J:106040 )

• mature B cell numbers are greatly reduced in bone marrow, spleen and liver of homozygous mutant mice

decreased B-1a cell number ( J:106040 )

• the intraperitoneal B1 cell population is skewed toward B1b cells (CD5^-), with concomitant reduction of the proportion of B1a cells (CD5⁺) from the 30-40% seen in wild-type mice to ~10-20% in homozygous mutants

decreased pre-B cell number ( J:106040 )

• numbers of bone marrow pre-B cells (Lin^-IgM^-B220⁺CD43^-) are greatly reduced

abnormal T cell subpopulation ratio ( J:106040 )

• the proportion of immature, CD4^-CD8^- (double negative, DN) thymocytes is elevated

• within the DN thymocyte population, the proportions of early, DN1-DN2 stage thymocytes are elevated, while later, DN3-DN4 stage thymocyte percentages are reduced

• mutant thymi contain elevated numbers of the earliest T cell lineage-restricted progenitor cells (ETPs, CD3^-CD4^-CD8^-Kit^bright), but reduced numbers of proT and preT cells

decreased T cell number ( J:106040 )

• numbers of mature CD4⁺ and CD8⁺ T cells in the periphery are slightly reduced in mutant mice

decreased thymocyte number ( J:106040 )

• thymi of mutant mice contain 3.4-fold fewer thymocytes than those of wild-type mice

increased lymphocyte cell number ( J:106040 )

• intraperitoneal lymphocyte numbers in mutant mice increase progressively with age, to greater than 3-fold wild-type numbers by 4-8 months

increased B-1 B cell number ( J:106040 )

• the percentage of physically and functionally normal B1 cells (Mac1^lowIgM^highCD43⁺B7.1⁺CD23^-CD19⁺B220^low) in the peritoneum increases with time

• B1 cells account for up to 43% of peripheral blood lymphocytes in older mutant mice, although they are not present in blood of wild-type mice

• Southern blot analysis of peritoneal lymphocytes for IghD-J rearrangements found evidence of clonal B1 cell proliferation in one mutant mouse of 6 studied at ages 6-8 mo

increased B-1b cell number ( J:106040 )

• the intraperitoneal B1 cell population is skewed toward B1b cells (CD5^-), with concomitant reduction of the proportion of B1a cells (CD5⁺) from the 30-40% seen in wild-type mice to ~10-20% in homozygous mutants

increased T cell number ( J:106040 )

• peripheral blood T-lymphocyte numbers are greatly elevated in 40% of mice with thymic lymphoma

increased IgM level ( J:106040 )

• circulating IgM levels in mutant mice are elevated to 3-fold wild-type levels