Alternative titles; symbols
HGNC Approved Gene Symbol: SPI1
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38): 11:47,354,860-47,378,547 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p11.2 | Agammaglobulinemia 10, autosomal dominant | 619707 | Autosomal dominant | 3 |
The SPI1 gene encodes a transcription factor essential for the development of multiple hematopoietic lineages (Scott et al., 1994).
Moreau-Gachelin et al. (1988) reported the characterization of a putative oncogene isolated from a murine erythroleukemia induced by the acute leukemogenic retrovirus spleen focus forming virus (SFFV). The genomic locus was called Spi1, for SFFV proviral integration. Rearrangements due to SFFV integration were found in 95% of the erythroid tumors studied. A 4.0-kb mRNA was detected in rearranged tumors. The evolutionary conservation of the SPI1 locus was examined in cellular DNAs from various vertebrate species. EcoRI fragments that hybridized with a probe from the locus were present in DNA digests from birds and several mammals, including man.
Ray et al. (1990) reported that the SPI1 gene encodes a deduced 264-amino acid protein that shares 88% sequence identity with the murine counterpart.
In human bone marrow, Le Coz et al. (2021) found expression of the SPI1 gene in hematopoietic stem cells, lymphoid progenitors, myeloid lineage cells, and B-cell clusters, with pre-B1 cells expressing the most SPI1 protein.
Ray et al. (1990) identified 5 exons in the SPI1 gene.
Nguyen et al. (1989, 1990) mapped the SPI1 oncogene to chromosome 11 by somatic cell hybrid analysis and regionalized it to chromosome 11p11.22 by in situ hybridization.
Spi1 (and Sfpi1) is also known as PU.1. It is an ETS-domain transcription factor essential for the development of myeloid and B-lymphoid cells. In myeloid cells, PU.1 is thought to regulate transcription of both FMS (164770) and CD18/11B (600065) proteins that are central to the osteoclast phenotype. The similarities between macrophages and osteoclasts, and the critical role PU.1 plays in generating myeloid cells (which are osteoclast progenitors), suggested to Tondravi et al. (1997) that failure to express PU.1 might preclude development of osteoclasts, leading to arrested bone resorption and osteopetrosis. The investigators showed that PU.1 mRNA progressively increases as marrow macrophages assume the osteoclast phenotype in vitro. The association between PU.1 and osteoclast differentiation was confirmed by demonstrating that PU.1 expression increased with the induction of osteoclastogenesis by either 1,25-dihydroxyvitamin D3 or dexamethasone.
Li et al. (1997) showed that PU.1 is required for p47-phox (608512) promoter activity in myeloid cells.
DeKoter and Singh (2000) used retroviral transduction of PU.1 cDNA into mutant hematopoietic progenitors to demonstrate that differing concentrations of the protein regulate the development of B lymphocytes as compared with macrophages. A low concentration of PU.1 protein induces the B cell fate, whereas a high concentration promotes macrophage differentiation and blocks B cell development. Conversely, a transcriptionally weakened mutant protein preferentially induces B cell generation. DeKoter and Singh (2000) concluded that graded expression of a transcription factor can be used to specify distinct cell fates in the hematopoietic system.
DeKoter et al. (2002) showed that hemopoietic progenitor cells lacking PU.1 failed to express interleukin-7 receptor-alpha (IL7R; 146661) transcripts. Promoter and crosslinking analyses suggested that PU.1 directly regulates IL7R transcription. Expression of IL7R in PU.1 -/- progenitors restored IL7 (146660)-dependent proliferation and induced, at low frequency, the generation of pro-B cells that underwent an apparently normal differentiation program. SPIB (606802) could substitute for PU.1 early in B-cell development, but it was not required. DeKoter et al. (2002) concluded that PU.1 partially controls early B-cell development by regulating the expression of IL7R.
Using FACS analysis, Zou et al. (2005) showed that knocking down Pu.1 in mouse hemopoietic progenitor cells (HPCs) with small interfering RNA (siRNA) induced coexpression of early B-cell lineage commitment markers Cd19 (107265) and Cd45r (PTPRC; 151460). Western blot analysis demonstrated that expression of the transcription factors Ebf (164343) and Pax5 (167414) was induced in the Pu.1-knockdown cells. These effects were also found in Cd34 (142230)-positive embryoid body cells treated with Pu.1-specific siRNA, as measured by enhanced expression of Cd19, Cd43 (SPN; 182160), and Cd45r. Zou et al. (2005) concluded that constitutive Pu.1 expression inhibits the earliest B-cell development through repression of EBF and PAX5, and that lower levels of Pu.1 expression in HPCs are key in promoting B-cell fate determination.
Tight regulation of transcription factors, such as PU.1, is critical for generation of all hematopoietic lineages. Rosenbauer et al. (2004) reported that mice with a deletion of the upstream regulatory element (URE) of the PU.1 (Sfpi1) gene developed acute myeloid leukemia. The URE is located 14-kb upstream of the mouse Pu.1 gene and 16-kb upstream of the human PU.1 gene. Rosenbauer et al. (2006) showed that the URE has an essential role in orchestrating the dynamic PU.1 expression pattern required for lymphoid development and tumor suppression. They presented results that elucidated how a single transcription factor, PU.1, through the cell context-specific activity of a key cis-regulatory element, affects the development of multiple cell lineages and can induce cancer.
Steidl et al. (2007) identified the transcriptional regulator SATB1 (602075) as a long-range positive regulator of PU.1 and demonstrated that SATB1 acts through the URE located approximately 16 kb upstream of the PU.1 transcriptional start site. Through studies of Satb1-null mice, SATB1 appeared to act at specific points during myeloid development.
Rosa et al. (2007) identified a pathway by which PU.1 regulated human monocyte/macrophage differentiation. PU.1 activated transcription of MIRN424 (300682), which translationally repressed NFIA (600727), resulting in activation of differentiation-specific genes, such as MCSFR (CSF1R; 164770).
Chang et al. (2010) found that conditional deletion of Pu1 in mouse T cells or small interfering RNA against PU1 in human T cells impaired IL9 (146931) production, whereas ectopic PU1 promoted IL9 production. Mice with Pu1-deficient T cells developed normal Th2 responses in vivo, but they showed allergic pulmonary inflammation corresponding to lower Il9 expression and chemokine production in peripheral T cells and lungs. Chang et al. (2010) concluded that PU1 has a critical role in generating Th9 cells and in the development of allergic inflammation.
Mossadegh-Keller et al. (2013) demonstrated that macrophage colony-stimulating factor (CSF1; 120420), a myeloid cytokine released during infection and inflammation, can directly induce the myeloid master regulator PU.1 and instruct myeloid cell-fate change in mouse HSCs, independently of selective survival or proliferation. Video imaging and single-cell gene expression analysis revealed that stimulation of highly purified hematopoietic stem cells with CSF1 in culture results in activation of the PU.1 promoter and an increased number of PU.1-positive cells with myeloid gene signature and differentiation potential. In vivo, high systemic levels of CSF1 directly stimulated CSF1-receptor-dependent activation of endogenous PU.1 protein in single hematopoietic stem cells and induced a PU.1-dependent myeloid differentiation preference. Mossadegh-Keller et al. (2013) concluded that their data demonstrated that lineage-specific cytokines can act directly on hematopoietic stem cells in vitro and in vivo to instruct a change of cell identity. The authors concluded that this observation fundamentally changed the view of how hematopoietic stem cells respond to environmental challenge and implicated stress-induced cytokines as direct instructors of hematopoietic stem cell fate.
Hoppe et al. (2016) used novel reporter mouse lines and live imaging for continuous single-cell long-term quantification of the transcription factors GATA1 (305371) and PU.1 and analyzed individual hematopoietic stem cells throughout differentiation into megakaryocytic-erythroid and granulocytic-monocytic lineages. The observed expression dynamics were incompatible with the assumption that stochastic switching between PU.1 and GATA1 precedes and initiates megakaryocytic-erythroid versus granulocytic-monocytic lineage decision-making. Rather, the findings suggested that these transcription factors are only executing and reinforcing lineage choice once made. Hoppe et al. (2016) concluded that their results challenged the prevailing model of early myeloid lineage choice, which assumed that lineage choice is initiated and determined by stochastic fluctuations of cross-antagonistic transcription factor pairs.
Batista et al. (2017) found that mice with deletion of both Pu.1 and Spib showed impaired B-cell development with blocked transition from small pre-B cells to immature B cells in bone marrow, in contrast with normal B-cell development and mild impairment of B-cell function in mice lacking Pu.1 or Spib in the B-cell lineage. Analysis with the pro-B cell line i660BM identified genes involved in B-cell receptor signaling, as well as Ig recombination and/or accessibility, as target genes directly regulated by Pu.1. Induced Pu.1 expression promoted transcription and rearrangement of the Ig-kappa locus in cultured pro-B cells in vitro, whereas Ig-kappa transcription was reduced in vivo in bone marrow pre-B cells from mice lacking both Pu.1 and Spib. The authors concluded that Pu.1 regulates Ig-kappa transcription and rearrangement in pre-B cells during B-cell development.
Potential Role in Malignancy
Steidl et al. (2007) identified a germline T-to-G SNP in the first homology region of the URE of the PU.1 gene in humans that was 2.5 times more frequent in patients with acute myelogenous leukemia (AML; 601626) and complex karyotypes compared to patients with AML and normal karyotypes. They found that the T-to-G SNP in the URE inhibited binding of SATB1 and thus downregulated PU.1 expression. Bone marrow myeloid precursor cells derived from AML patients carrying the homozygous SNP showed decreased PU.1 expression. Steidl et al. (2007) concluded that this SNP may act specifically as a modifier for the subtype of AML with abnormal karyotype.
By direct sequencing, Bonadies et al. (2010) did not detect mutations in the URE of the PU.1 gene in malignant cells of 120 patients with AML. Loss of heterozygosity (LOH) analysis at this locus in 23 patients studied at diagnosis and at remission identified 1 patient with AML type M2 who was heterozygous for a 4-kb segment encompassing the promoter region up to exon 4 of the PU.1 gene at remission but had LOH of this region at diagnosis. PU.1 expression was markedly decreased in this patient compared to controls. The findings suggested that heterozygous loss of PU.1 can be associated with AML.
Autosomal Dominant Agammaglobulinemia 10
In 6 unrelated patients with autosomal dominant agammaglobulinemia-10 (AGM10; 619707), Le Coz et al. (2021) identified heterozygous mutations in the SPI1 gene (165170.0001-165170.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. There were 2 nonsense, 2 frameshift, and 2 missense mutations. Four were demonstrated to have occurred de novo; the mode of inheritance could not be determined in 2 patients. Patient cells showed decreased or absent SPI1 protein expression, consistent with a loss of function and haploinsufficiency. Analysis of patient leukocyte subsets found decreased levels of SPI1-expressing B cells and conventional dendritic cells (cDCs) compared to controls. Bone marrow derived from patient A showed only pro-B cells, indicating lineage arrest before the pre-B1 stage when SPI1 is highly expressed. Transcriptional analysis of patient cells showed decreased expression of a myriad of genes involved in B-cell development, migration, activation, and regulation. In vitro functional expression studies showed that if the mutant proteins were expressed, they had altered cellular localization, impaired transcriptional activity, and poor DNA binding. Other mutations caused transcript or protein degradation resulting in loss of protein expression. Further in vitro studies indicated that loss of SPI1 decreases open chromatin regions, thus reducing gene promoter access of transcription factors relevant to B-cell development. The findings were consistent with haploinsufficiency.
Scott et al. (1994) found that Pu.1-null mouse embryos died at a late gestational age. Examination of embryos showed severe anemia with impaired maturation of fetal erythrocytes, but normal numbers of megakaryocytes. Mutant mice also had a multilineage defect in the generation of progenitors for B cells, T cells, granulocytes, and monocytes. Other aspects of development appeared normal, suggesting that the effect was restricted to cells of the hematopoietic lineage. Heterozygous mutant mice were similar to wildtype.
Consistent with the participation of PU.1 in osteoclastogenesis, Tondravi et al. (1997) found that the development of both osteoclasts and macrophages was arrested in mice with disruption of the transcription factor gene by homologous recombination. Homozygous deficient mice were born alive but died of septicemia within 24 to 48 hours. Following intraperitoneal injection of marrow cells recovered from homozygous or heterozygous normal mice, the PU.1 knockout mice survived for at least 6 months and were grossly indistinguishable from wildtype littermates. All aspects of the osteopetrotic phenotype were reversed.
Sfpi1, encoding the lineage-specific transcription factor PU.1, is indispensable for normal myeloid and lymphoid development. Rosenbauer et al. (2004) 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, develop acute myeloid leukemia (AML; 601626). Unlike complete or 50% loss, 80% loss of PU.1 induced a precancerous state characterized by accumulation of an abnormal precursor pool retaining responsiveness to colony-stimulating factor GCSF (CSF3; 138970) with disruption of MCSF (CSF1; 120420) and GMCSF (CSF2; 138960) pathways. Malignant transformation was associated with a high frequency of clonal chromosomal changes. Retroviral restoration of PU.1 expression rescued myeloid differentiation of mutant progenitors and AML blasts. These results suggested that tightly graded reduction, rather than complete loss, of a lineage-indispensable transcription factor can induce AML.
Metcalf et al. (2006) conditionally deleted the Pu.1 gene in adult mice. After 13 weeks, Pu.1 -/- mice began dying of myeloid leukemia, and 95% of mice that survived early postinduction death developed transplantable myeloid leukemia. The leukemic cells formed autonomous colonies in semisolid culture, and colony formation was enhanced by IL3 (147740) and sometimes by GMCSF. Nine of 13 tumors analyzed developed a capacity for autocrine Il3 or Gmcsf production, and there was evidence of rearrangement of the Il3 gene.
Huang et al. (2008) found that AML1 (RUNX1; 151385) bound to 3 conserved sites in the mouse Pu.1 URE in vitro and in vivo and regulated Pu.1 expression at both embryonic and adult stages of hematopoietic development. Using conditional Aml1 knockout alleles and knockin mice carrying mutations in all 3 Aml1-binding sites, they demonstrated that Aml1 regulated Pu.1 expression both positively and negatively in a lineage-dependent manner. The effect of loss of Aml1 in each lineage was partially rescued by restoring or decreasing Pu.1 expression levels, suggesting that PU.1 is a critical downstream target of AML1 in adult hematopoiesis.
Carotta et al. (2014) found that deletion of both Irf8 (601565) and Pu.1 in B cells of mice resulted in a dramatic enhancement in the rates of class switch recombination (CSR) and antibody-secreting cell (ASC) differentiation. Irf8/Pu.1 controlled the B cell-to-ASC transition by simultaneously activating components of the B-cell program, including Bcl6 (109565), and repressing ASC-promoting factors, such as Prdm1 (603423). The authors found that Irf4 (601900), which promotes CSR and ASC differentiation, bound the same sites as Irf8 in critical target genes. Carotta et al. (2014) proposed that the rate of ASC differentiation is controlled by the relative concentrations of IRF4 and IRF8 acting in a reciprocal manner.
In a 15-month-old boy (patient A) with autosomal dominant agammaglobulinemia-10 (AGM10; 619707), Le Coz et al. (2021) identified a de novo heterozygous c.325_327delGGCinsAG mutation (c.325_327delGGCinsAG, NM_001080547.2) in the SPI1 gene, resulting in a frameshift and premature termination (Gly109SerfsTer78). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Patient cells showed loss of SPI1 protein expression, consistent with a loss of function and haploinsufficiency.
In a 7-year-old boy (patient B) with autosomal dominant agammaglobulinemia-10 (AGM10; 619707), Le Coz et al. (2021) identified a de novo heterozygous c.331C-T transition (c.331C-T, NM_001080547.2) in the SPI1 gene, resulting in a gln111-to-ter (Q111X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Patient cells showed loss of SPI1 protein expression, consistent with a loss of function and haploinsufficiency.
In a 37-year-old man (patient C) with autosomal dominant agammaglobulinemia-10 (AGM10; 619707), Le Coz et al. (2021) identified a de novo heterozygous c.366C-A transversion (c.366C-A, NM_001080547.2) in the SPI1 gene, resulting in a tyr122-to-ter (Y122X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Patient cells showed loss of SPI1 protein expression, consistent with a loss of function and haploinsufficiency.
In a 32-year-old man (patient D) with autosomal dominant agammaglobulinemia-10 (AGM10; 619707), Le Coz et al. (2021) identified a de novo heterozygous c.635A-C transversion (c.635A-C, NM_001080547.2) in the SPI1 gene, resulting in a his212-to-pro (H212P) substitution at a conserved residue in the ETS domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. HEK293 cells transfected with the mutation showed decreased protein levels, impaired transcriptional activity, and decreased DNA binding compared to controls, consistent with a loss of function.
In an 8-year-old boy (patient E) with autosomal dominant agammaglobulinemia-10 (AGM10; 619707), Le Coz et al. (2021) identified a heterozygous 2-bp deletion in the SPI1 gene (c.696_697delGC, NM_001080547.2), resulting in a frameshift and premature termination (Leu233AlafsTer53). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The patient's unaffected mother did not carry the mutation. DNA from the father was unavailable. HEK293 cells transfected with the mutation showed decreased protein levels, altered cellular localization, impaired transcriptional activity, and decreased DNA binding compared to controls, consistent with a loss of function.
Batista, C. R., Li, S. K., Xu, L. S., Solomon, L. A., DeKoter, R. P. PU.1 regulates Ig light chain transcription and rearrangement in pre-B cells during B cell development. J. Immun. 198: 1565-1574, 2017. [PubMed: 28062693] [Full Text: https://doi.org/10.4049/jimmunol.1601709]
Bonadies, N., Pabst, T., Mueller, B. U. Heterozygous deletion of the PU.1 locus in human AML. Blood 115: 331-334, 2010. [PubMed: 19890096] [Full Text: https://doi.org/10.1182/blood-2009-03-212225]
Carotta, S., Willis, S. N., Hasbold, J., Inouye, M., Pang, S. H. M., Emslie, D., Light, A., Chopin, M., Shi, W., Wang, H., Morse, H. C., III, Tarlinton, D. M., Corcoran, L. M., Hodgkin, P. D., Nutt, S. L. The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation. J. Exp. Med. 211: 2169-2181, 2014. [PubMed: 25288399] [Full Text: https://doi.org/10.1084/jem.20140425]
Chang, H.-C., Sehra, S., Goswami, R., Yao, W., Yu, Q., Stritesky, G. L., Jabeen, R., McKinley, C., Ahyi, A.-N., Han, L., Nguyen, E. T., Robertson, M. J., Perumal, N. B., Tepper, R. S., Nutt, S. L., Kaplan, M. H. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nature Immun. 11: 527-534, 2010. [PubMed: 20431622] [Full Text: https://doi.org/10.1038/ni.1867]
DeKoter, R. P., Lee, H.-J., Singh, H. PU.1 regulates expression of the interleukin-7 receptor in lymphoid progenitors. Immunity 16: 297-309, 2002. [PubMed: 11869689] [Full Text: https://doi.org/10.1016/s1074-7613(02)00269-8]
DeKoter, R. P., Singh, H. Regulation of B lymphocyte and macrophage development by graded expression of PU.1. Science 288: 1439-1441, 2000. [PubMed: 10827957] [Full Text: https://doi.org/10.1126/science.288.5470.1439]
Hoppe, P. S., Schwarzfischer, M., Loeffler, D., Kokkaliaris, K. D., Hilsenbeck, O., Moritz, N., Endele, M., Filipczyk, A., Gambardella, A., Ahmed, N., Etzrodt, M., Coutu, D. L., and 11 others. Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios. Nature 535: 299-302, 2016. [PubMed: 27411635] [Full Text: https://doi.org/10.1038/nature18320]
Huang, G., Zhang, P., Hirai, H., Elf, S., Yan, X., Chen, Z., Koschmieder, S., Okuno, Y., Dayaram, T., Growney, J. D., Shivdasani, R. A., Gilliland, D. G., Speck, N. A., Nimer, S. D., Tenen, D. G. PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. Nature Genet. 40: 51-60, 2008. Note: Erratum: Nature Genet. 40: 255 only, 2008. [PubMed: 17994017] [Full Text: https://doi.org/10.1038/ng.2007.7]
Le Coz, C., Nguyen, D. N., Su, C., Nolan, B. E., Albrecht, A. V., Xhani, S., Sun, D., Demaree, B., Pillarisetti, P., Khanna, C., Wright, F., Chen, P. A., and 33 others. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients. J. Exp. Med. 218: e20201750, 2021. [PubMed: 33951726] [Full Text: https://doi.org/10.1084/jem.20201750]
Li, S.-L., Valente, A. J., Zhao, S.-J., Clark, R. A. PU.1 is essential for p47(phox) promoter activity in myeloid cells. J. Biol. Chem. 272: 17802-17809, 1997. [PubMed: 9211934] [Full Text: https://doi.org/10.1074/jbc.272.28.17802]
Metcalf, D., Dakic, A., Mifsud, S., Di Rago, L., Wu, L., Nutt, S. Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia. Proc. Nat. Acad. Sci. 103: 1486-1491, 2006. [PubMed: 16432184] [Full Text: https://doi.org/10.1073/pnas.0510616103]
Moreau-Gachelin, F., Tavitian, A., Tambourin, P. Spi-1 is a putative oncogene in virally induced murine erythroleukaemias. Nature 331: 277-280, 1988. [PubMed: 2827041] [Full Text: https://doi.org/10.1038/331277a0]
Mossadegh-Keller, N., Sarrazin, S., Kandalla, P. K., Espinosa, L., Stanley, E. R., Nutt, S. L., Moore, J., Sieweke, M. H. M-CSF instructs myeloid lineage fate in single haematopoietic stem cells. Nature 497: 239-243, 2013. [PubMed: 23575636] [Full Text: https://doi.org/10.1038/nature12026]
Nguyen, V. C., Moreau-Gachelin, F., Ray, D., Gross, M. S., de Tand, M. F., Tavitian, A., Frezal, J. Assignment of SPI1 oncogene to chromosome 11 (somatic cell hybrid analysis), region p11.22 (in situ hybridization). (Abstract) Cytogenet. Cell Genet. 51: 1097 only, 1989.
Nguyen, V. C.., Ray, D., Gross, M. S., de Tand, M. F., Frezal, J., Moreau-Gachelin, F. Localization of the human oncogene SPI1 on chromosome 11, region p11.22. Hum. Genet. 84: 542-546, 1990. [PubMed: 2338340] [Full Text: https://doi.org/10.1007/BF00210807]
Ray, D., Culine, S., Tavitian, A., Moreau-Gachelin, F. The human homologue of the putative proto-oncogene Spi-1: characterization and expression in tumors. Oncogene 5: 663-667, 1990. Note: Erratum: Oncogene 5: 1611-1612, 1990. [PubMed: 1693183]
Rosa, A., Ballarino, M., Sorrentino, A., Sthandier, O., De Angelis, F. G., Marchioni, M., Masella, B., Guarini, A., Fatica, A., Peschle, C., Bozzoni, I. The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation. Proc. Nat. Acad. Sci. 104: 19849-19854, 2007. [PubMed: 18056638] [Full Text: https://doi.org/10.1073/pnas.0706963104]
Rosenbauer, F., Owens, B. M., Yu, L., Tumang, J. R., Steidl, U., Kutok, J. L., Clayton, L. K., Wagner, K., Scheller, M., Iwasaki, H., Liu, C., Hackanson, B., Akashi, K., Leutz, A., Rothstein, T. L., Plass, C., Tenen, D. G. Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. Nature Genet. 38: 27-37, 2006. [PubMed: 16311598] [Full Text: https://doi.org/10.1038/ng1679]
Rosenbauer, F., Wagner, K., Kutok, J. L., Iwasaki, H., Le Beau, M. M., Okuno, Y., Akashi, K., Fiering, S., Tenen, D. G. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nature Genet. 36: 624-630, 2004. [PubMed: 15146183] [Full Text: https://doi.org/10.1038/ng1361]
Scott, E. W., Simon, M. C., Anastasi, J., Singh, H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265: 1573-1577, 1994. [PubMed: 8079170] [Full Text: https://doi.org/10.1126/science.8079170]
Steidl, U., Steidl, C., Ebralidze, A., Chapuy, B., Han, H.-J., Will, B., Rosenbauer, F., Becker, A., Wagner, K., Koschmieder, S., Kobayashi, S., Costa, D. B., and 10 others. A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. J. Clin. Invest. 117: 2611-2620, 2007. [PubMed: 17694175] [Full Text: https://doi.org/10.1172/JCI30525]
Tondravi, M. M., McKercher, S. R., Anderson, K., Erdmann, J. M., Quiroz, M., Maki, R., Teitelbaum, S. L. Osteopetrosis in mice lacking haematopoietic transcription factor PU.1 Nature 386: 81-84, 1997. [PubMed: 9052784] [Full Text: https://doi.org/10.1038/386081a0]
Zou, G.-M., Chen, J.-J., Yoder, M. C., Wu, W., Rowley, J. D. Knockdown of Pu.1 by small interfering RNA in CD34+ embryoid body cells derived from mouse ES cells turns cell fate determination to pro-B cells. Proc. Nat. Acad. Sci. 102: 13236-13241, 2005. [PubMed: 16141339] [Full Text: https://doi.org/10.1073/pnas.0506218102]