Heterozygous deletion of the PU.1 locus in human AML

Bonadies, Nicolas; Pabst, Thomas; Mueller, Beatrice U.

doi:10.1182/blood-2009-03-212225

Cited by 31 publications

(30 citation statements)

References 23 publications

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“…Therefore, the cooperation between Sox4 and Sfpi1 haploinsufficiency in inducing myeloid leukemia is at least in part caused by a further decrease in Sfpi1 expression in myeloid progenitors because of direct transcriptional repression of the residual Sfpi1 allele by Sox4. Heterozygous PU.1 mutations have been found to be associated with some human AMLs 30,31 ; our results suggest that activation of SOX4 could be a mechanism to further downregulate PU.1 in these patients. Our identification of Sfpi1 as a repression target for Sox4 may also explain the Sox4-induced block of myeloid differentiation previously observed in 32Dcl.3 cells.…”

Section: Sox4 Cooperates With Reduced Sfpi1 Expression In Myeloid Leumentioning

confidence: 53%

Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia

Aue

Cleveland

et al. 2011

Blood

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Cooperation of multiple mutations is thought to be required for cancer development. In previous studies, murine myeloid leukemias induced by transducing wild-type bone marrow progenitors with a SRY sex determining region Y-box 4 (Sox4)-expressing retrovirus frequently carried proviral insertions at Sfpi1, decreasing its mRNA levels, suggesting that reduced Sfpi1 expression cooperates with Sox4 in myeloid leukemia induction. In support of this hypothesis, we show here that mice receiving Sox4 virus-infected Sfpi1 ko/؉ bone marrow progenitors developed myeloid leukemia with increased penetrance and shortened latency. Interestingly, Sox4 expression further decreased Sfpi1 transcription. Ectopic SOX4 expression reduced endogenous PU.1 mRNA levels in HL60 promyelocytes, and decreased Sfpi1 mRNA levels were also observed in the spleens of leukemic and preleukemic mice receiving Sox4 virus-infected wild-type bone marrow cells. In addition, Sox4 protein bound to a critical upstream regulatory element of Sfpi1 in ChIP assays. Such cooperation probably occurs in de novo human acute myeloid leukemias, as an analysis of 285 acute myeloid leukemia patient samples found a significant negative correlation between SOX4 and PU.1 expression. 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. (Blood. 2011;118(17):4674-4681) IntroductionSRY sex determining region Y-box 4 (Sox4) is a member of the SOX (SRY-related HMG-box) transcription factor family and is an important regulator of mammalian development. Homozygous deletion of Sox4 in mice results in embryonic lethality because of defective formation of the cardiac outflow tract. 1 B-and T-cell development in these Sox4-deficient embryos is also severely impaired, indicating that Sox4 function is critical for normal differentiation and expansion of the lymphoid lineages. 1,2 A role for Sox4 in cancer development was first suggested by the identification of viral insertions, activating Sox4 expression in leukemias developing in inbred strains of mice carrying endogenous retroviruses. 3 Overexpression of Sox4 was also found to block differentiation of 32Dcl.3 myeloid progenitor cells. 4 Sox4 was confirmed as an oncogene when transplantation of primary mouse bone marrow cells infected with a Sox4-expressing retroviral vector resulted in myeloid leukemia development in recipient mice. 3 The link between SOX4 and oncogenesis is not limited to leukemias, as it was also found to be overexpressed in human solid tumors, including medulloblastoma, 5 colon, 6 prostate, 7 and lung cancers. 8 However, despite overexpression of SOX4 in these tumors, a tumor-suppressive function for SOX4 has also been suggested in lung and bladder cancer cell lines, 7,9 reflecting a potential cell context-dependent role of SOX4 in tumorigenesis.There is a paucity of data about the molecular mechanisms through which SOX4 can exert an oncogenic function...

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Section: Sox4 Cooperates With Reduced Sfpi1 Expression In Myeloid Leumentioning

confidence: 53%

Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia

Aue

Cleveland

et al. 2011

Blood

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“…Heterozygous inactivating mutations of the gene encoding human PU.1 (SPI1) have been identified in acute myeloid leukemia (AML) patients (Bonadies et al 2010;Link et al 2007;Mueller et al 2002). In addition, PU.1 expression is frequently suppressed in AML by the altered protein products of chromosomal translocations (Vangala et al 2003).…”

Section: Pu1 Levels and Disease: A Unified Perspectivementioning

confidence: 99%

The Transcription Factor PU.1 is a Critical Regulator of Cellular Communication in the Immune System

Turkistany

DeKoter

2011

Arch. Immunol. Ther. Exp.

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PU.1 is an E26 transformation-specific family transcription factor that is required for development of the immune system. PU.1 functions at both early and late stages of lymphoid and myeloid differentiation. At least 110 direct target genes of PU.1 have been identified since its discovery in 1988. We used the published literature to determine if aspects of PU.1 function can be inferred from the identity of target genes that are directly activated. This analysis revealed that 61% of described PU.1 target genes encode extracellular proteins or transmembrane proteins, most of which are involved in cellular communication. The genes activated by PU.1 can be grouped into pathways based on function. Specific examples of cellular communication pathways regulated by PU.1 include (1) antibodies and antibody receptors, (2) cytokines and cytokine receptors regulating leukocyte growth and development, and (3) cytokines and cytokine receptors regulating inflammation. As a consequence of mutation or repression of the gene encoding PU.1, hematopoietic progenitors may be generated but there is a "failure to thrive" because they cannot interact with their environment. The loss of cellular communication caused by reduced PU.1 levels can lead to leukemia. In summary, PU.1 is a critical regulator of cellular communication in the immune system.

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“…Functionally critical decreases in PU.1 levels have been described in FLT3-internal tandem duplication (FLT3-ITD) (3), RUNX1-ETO (4), and promyelocytic leukemia (5), representing 24%, 7%, and 13% of all AMLs, respectively (cancer.sanger.ac.uk) (6,7). Additionally, PU.1 loss-of-function heterozygous mutations or deletions have been described in AML and are found in approximately 10% of MLL-translocated AMLs (8)(9)(10). Homozygosity of a single nucleotide variant in an upstream regulatory element (URE) of PU.1, lowering PU.1 expression, has been described in AML with complex karyotype (11), and a study on highly purified stem cells from patients with AML showed reduced PU.1 levels in at least 40% of examined cases (12).…”

Section: Introductionmentioning

confidence: 99%