C/EBP-β, C/EBP-δ, PU.1, AML1 genes: mutational analysis in 381 samples of hematopoietic and solid malignancies

Vegesna, Vijaya; Takeuchi, Seisho; Hofmann, Werner; Ikezoe, Takayuki; Tavor, Sigal; Krug, Utz; Fermin, Anthony C; Heaney, Anthony P.; Miller, Carl W.; Koeffler, H. Phillip

doi:10.1016/s0145-2126(01)00150-3

Cited by 54 publications

(44 citation statements)

References 27 publications

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“…Therefore, the increased expression of C/EBP ß may be related to the proliferation and invasiveness of glioma. Very few mutations in C/EBP ß were identified in a survey of 381 cancers and cell lines representing leukemias, lymphomas, and various solid tumors (39). Only 2 of the 381 samples had missense mutations and 2 others had silent mutations.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of CCAAT/enhancer binding protein β correlates with prognosis in glioma patients

Homma

Yamanaka²,

Yajima³

et al. 2006

Oncol Rep

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Abstract. C/EBP ß (CCAAT/enhancer binding protein ß) is a transcriptional factor that belongs to the basic region-leucine zipper class DNA-binding proteins and plays a role in cell differentiation and inflammatory reactions. Although high tissue levels of inflammatory cytokines, such as interleukin (IL)-6, IL-8 and transforming growth factor-ß, have been observed in glioma patients, the mechanisms underlying this phenomenon remain to be elucidated. C/EBP ß induces a variety of cytokines and thus may play a role in the pathogenesis of glioma. In this study, we investigated the relationship between C/EBP ß expression, tumor histology, and prognosis in glioma. The expression of C/EBP ß mRNA was examined with quantitative real-time PCR and protein expression was examined with immunohistochemical techniques in 47 glioma tissue samples. Expression of C/EBP ß mRNA and protein was markedly increased in high grade glioma compared with low grade glioma. Patients whose expression of C/EBP ß mRNA and protein in tumor tissue was lower survived longer than those whose expressions were higher. In vitro, C/EBP ß siRNA inhibited glioma cell proliferation and invasion. Moreover, IL-8 production by glioma cells was inhibited by C/EBP ß siRNA transfection. These data suggest that increased expression of C/EBP ß may contribute to the promotion of tumor invasiveness and progression. The data imply that the comparison of C/EBP ß expression could be a prognostic marker for patients with glioma.

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Section: Discussionmentioning

confidence: 99%

Increased expression of CCAAT/enhancer binding protein β correlates with prognosis in glioma patients

Homma

Yamanaka²,

Yajima³

et al. 2006

Oncol Rep

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“…To our knowledge, screening for PU.1 mutations has been performed in four main studies, including altogether 262 AML patients. [168][169][170][171] PU.1 mutations were found in only 9 of those 262 AML patients (all in the study by Mueller et al 168 ), showing that PU.1 mutations rarely contribute to AML pathogenesis.…”

Section: Other Mutated Genesmentioning

confidence: 95%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

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Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

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“…Although we cannot exclude certain types of change such as large heterozygous deletions, no mutations were found in regions upstream of the human PU.1 promoter that are highly conserved between humans and mice, and may have a regulatory function. These data, and the failure to find mutation at the R235 residue in over 600 human AMLs (Lamandin et al, 2002;Mueller et al, 2002;Vegesna et al, 2002;Dohner et al, 2003;Ley et al, 2003;Mueller et al, 2003), suggest that the leukaemogenic mechanism observed in the mouse are unique to this model system. However, it is possible that mutation of R235 may occur in those very few human AMLs that do show LOH of PU.1 (Mitelman et al, 1997).…”

mentioning

confidence: 96%

“…Biallelic mutations were rare (2/9) as the majority of AMLs with mutations retained the wildtype allele. However, the frequency with which PU.1 mutations arise in AML remains contentious, because multiple subsequent studies have failed to identify a single mutation (Lamandin et al, 2002;Vegesna et al, 2002;Dohner et al, 2003;Ley et al, 2003;Mueller et al, 2003). As the AMLs analysed were primarily de novo (the study of Vegesna et al and Lamandin et al excluded therapy(t)-related AML), it is possible that mutation of PU.1 may arise more frequently in secondary or tAML than de novo AML; tAML is a known consequence of radio-and chemotherapy (Leone et al, 1999;Smith, 2003).…”

mentioning

confidence: 99%

Mutations of the PU.1 Ets domain are specifically associated with murine radiation-induced, but not human therapy-related, acute myeloid leukaemia

Suraweera

Meijne

Moody³

et al. 2005

Oncogene

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Murine radiation-induced acute myeloid leukaemia (AML) is characterized by loss of one copy of chromosome 2. Previously, we positioned the critical haematopoietic-specific transcription factor PU.1 within a minimally deleted region. We now report a high frequency (>65%) of missense mutation at codon 235 in the DNAbinding Ets domain of PU.1 in murine AML. Earlier studies, outside the context of malignancy, determined that conversion of arginine 235 (R235) to any other amino-acid residue leads to ablation of DNA-binding function and loss of expression of downstream targets. We show that mutation of R235 does not lead to protein loss, and occurs specifically in those AMLs showing loss of one copy of PU.1 (P ¼ 0.001, Fisher's exact test). PU.1 mutations were not found in the coding region, UTRs or promoter of human therapy-related AMLs. Potentially regulatory elements upstream of PU.1 were located but no mutations found. In conclusion, we have identified the cause of murine radiation-induced AML and have shown that loss of one copy of PU.1, as a consequence of flanking radiation-sensitive fragile domains on chromosome 2, and subsequent R235 conversion are highly specific to this mouse model. Such a mechanism does not operate, or is extremely rare, in human AML.

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C/EBP-β, C/EBP-δ, PU.1, AML1 genes: mutational analysis in 381 samples of hematopoietic and solid malignancies

Cited by 54 publications

References 27 publications

Increased expression of CCAAT/enhancer binding protein β correlates with prognosis in glioma patients

Increased expression of CCAAT/enhancer binding protein β correlates with prognosis in glioma patients

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

Mutations of the PU.1 Ets domain are specifically associated with murine radiation-induced, but not human therapy-related, acute myeloid leukaemia

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