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Low expression of interferon regulatory factor-1 and identification of novel exons skipping in patients with chronic myeloid leukaemia

Tzoanopoulos, D; Speletas, M; Arvanitidis, K; Veiopoulou, C; Kyriaki, S; Thyphronitis, G; Sideras, Paschalis LU ; Kartalis, G and Ritis, K (2002) In British Journal of Haematology 119(1). p.46-53
Abstract
Chronic myeloid leukaemia (CML) is a malignant clonal disorder of the haematopoietic stem cell. Treatment of CML patients with interferon alpha (IFN-alpha) has induced haematological and cytogenetic remission. Interferons transcriptionally activate target genes through the JAK-STAT and interferon regulated factors (IRFs) family pathways. Interferon regulated factor-1 (IRF-1) is a transcriptional activator of genes critical for cell growth, differentiation and apoptosis. The skipping of exons 2 or 2 and 3 of IRF-1 in patients with myelodysplastic syndromes and acute myelogenous leukaemia suggests that this factor may have a critical role in leukaemogenesis. The role of IRF-1 in CML is currently unknown. Therefore, mutational analysis of... (More)
Chronic myeloid leukaemia (CML) is a malignant clonal disorder of the haematopoietic stem cell. Treatment of CML patients with interferon alpha (IFN-alpha) has induced haematological and cytogenetic remission. Interferons transcriptionally activate target genes through the JAK-STAT and interferon regulated factors (IRFs) family pathways. Interferon regulated factor-1 (IRF-1) is a transcriptional activator of genes critical for cell growth, differentiation and apoptosis. The skipping of exons 2 or 2 and 3 of IRF-1 in patients with myelodysplastic syndromes and acute myelogenous leukaemia suggests that this factor may have a critical role in leukaemogenesis. The role of IRF-1 in CML is currently unknown. Therefore, mutational analysis of IRF-1 was performed and its expression pattern was also studied in CML patients. We studied IRF-1 in peripheral blood mononuclear cells of 21 patients in chronic phase CML. No point mutations were identified at the cDNA level. Surprisingly, fourfold reduction of full-length IRF-1 mRNA expression was established in 17/21 patients compared with normal individuals. Low expression of full-length IRF-1 was observed in conjunction with high levels of aberrantly spliced mRNAs, reported for the first time. In three patients who were also analysed during blastic transformation, further reduction of full-length IRF-1 mRNA was observed. These findings demonstrate that, in CML patients, IRF-1 can produce high levels of aberrant spliced mRNAs with subsequent reduction in the levels of full-length IRF-1 mRNA. This observation is consistent with the notion that exon skipping may constitute another mechanism of tumour suppressor gene inactivation in this disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
non-isotopic RNase cleavage assay, exon skipping, interferon, IRF-1, chronic myeloid leukaemia
in
British Journal of Haematology
volume
119
issue
1
pages
46 - 53
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • pmid:12358902
  • wos:000178348000007
  • scopus:0036401775
ISSN
0007-1048
DOI
10.1046/j.1365-2141.2002.03829.x
language
English
LU publication?
yes
id
99f8a96a-903e-4fe5-bfbe-3832d48c05aa (old id 327668)
date added to LUP
2007-11-16 13:56:07
date last changed
2017-01-01 04:58:44
@article{99f8a96a-903e-4fe5-bfbe-3832d48c05aa,
  abstract     = {Chronic myeloid leukaemia (CML) is a malignant clonal disorder of the haematopoietic stem cell. Treatment of CML patients with interferon alpha (IFN-alpha) has induced haematological and cytogenetic remission. Interferons transcriptionally activate target genes through the JAK-STAT and interferon regulated factors (IRFs) family pathways. Interferon regulated factor-1 (IRF-1) is a transcriptional activator of genes critical for cell growth, differentiation and apoptosis. The skipping of exons 2 or 2 and 3 of IRF-1 in patients with myelodysplastic syndromes and acute myelogenous leukaemia suggests that this factor may have a critical role in leukaemogenesis. The role of IRF-1 in CML is currently unknown. Therefore, mutational analysis of IRF-1 was performed and its expression pattern was also studied in CML patients. We studied IRF-1 in peripheral blood mononuclear cells of 21 patients in chronic phase CML. No point mutations were identified at the cDNA level. Surprisingly, fourfold reduction of full-length IRF-1 mRNA expression was established in 17/21 patients compared with normal individuals. Low expression of full-length IRF-1 was observed in conjunction with high levels of aberrantly spliced mRNAs, reported for the first time. In three patients who were also analysed during blastic transformation, further reduction of full-length IRF-1 mRNA was observed. These findings demonstrate that, in CML patients, IRF-1 can produce high levels of aberrant spliced mRNAs with subsequent reduction in the levels of full-length IRF-1 mRNA. This observation is consistent with the notion that exon skipping may constitute another mechanism of tumour suppressor gene inactivation in this disease.},
  author       = {Tzoanopoulos, D and Speletas, M and Arvanitidis, K and Veiopoulou, C and Kyriaki, S and Thyphronitis, G and Sideras, Paschalis and Kartalis, G and Ritis, K},
  issn         = {0007-1048},
  keyword      = {non-isotopic RNase cleavage assay,exon skipping,interferon,IRF-1,chronic myeloid leukaemia},
  language     = {eng},
  number       = {1},
  pages        = {46--53},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {British Journal of Haematology},
  title        = {Low expression of interferon regulatory factor-1 and identification of novel exons skipping in patients with chronic myeloid leukaemia},
  url          = {http://dx.doi.org/10.1046/j.1365-2141.2002.03829.x},
  volume       = {119},
  year         = {2002},
}