| 1. |
- Hedblom, Andreas, et al.
(författare)
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CDK1 interacts with RARγ and plays an important role in treatment response of acute myeloid leukemia
- 2013
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Ingår i: Cell Cycle. - : Taylor & Francis. - 1538-4101 .- 1551-4005. ; 12:8, s. 1251-1266
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Tidskriftsartikel (refereegranskat)abstract
- Alterations in cell cycle pathways and retinoic acid signaling are implicated in leukemogenesis. However, little is known about the roles of cyclin-dependent kinases (CDKs) in treatment response of leukemia. In this study, we observed that CDK1 expression was significantly higher in bone marrow from 42 patients with acute myeloid leukemia (AML) at recurrence than that at first diagnosis (p = 0.04). AML patients had higher level of nuclear CDK1 in their leukemic blasts tended to have poorer clinical outcome compared with those with lower levels. We showed that CDK1 function is required for all-trans retinoic acid (ATRA) to achieve the optimal effect in U-937 human leukemic cells. CDK1 modulates the levels of P27(kip) and AKT phosphorylation in response to ATRA treatment. Further, we show, for the first time, that RARγ in concert with ATRA regulates protein levels of CDK1 and its subcellular localization. The regulation of the subcellular content of CDK1 and RARγ by ATRA is an important process for achieving an effective response in treatment of leukemia. RARγ and CDK1 form a reciprocal regulatory circuit in the nucleus and influence the function and protein stability of each other and the level of P27(kip) protein. In addition, expression of wee1 kinase and Cdc25A/C phosphatases also coincide with CDK1 expression and its subcellular localization in response to ATRA treatment. Our study reveals a novel mechanism by which CDK1 and RARγ coordinate with ATRA to influence cell cycle progression and cellular differentiation.
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| 2. |
- Miftakhova, Regina, et al.
(författare)
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DNA Methylation in ATRA-treated leukemia cell lines lacking a PML-RAR chromosome translocation
- 2012
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Ingår i: Anticancer Research. - : International Institute of Anticancer Research. - 0250-7005 .- 1791-7530. ; 32:11, s. 4715-4722
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Tidskriftsartikel (refereegranskat)abstract
- Abstract A deficient retinoic acid signaling has been suggested to be an important cause of the clinical inefficacy of all-trans retinoic acid (ATRA) therapy in non-promyelocytic (non-PML) forms of acute myeloid leukemia (AML). The general aim of the present work was to explore novel ways to take advantage of the anti-leukemic potential of ATRA, and, specifically, to search for a synergism between ATRA and epigenetic drugs. Because previous reports have found no major influence of ATRA on DNA methylation, we investigated whether ATRA-mediated differentiation of the U937 and HL-60 AML cell lines, both lacking a PML-retinoic acid receptor (RAR) fusion product, is accompanied by early-appearing and weak changes in CpG methylation. We report that in HL-60 cells, by using a highly quantitative analysis of a set of genes found to be abnormally expressed in AML, polymerase chain reaction (PCR)-amplified p16 gene promoter molecules (each with 15 CpG sites), exhibited a CpG methylation level of 0-4% in untreated cells, which increased to 4-21% after treatment with ATRA for seven days. In contrast to HL-60 cells, U937 cells exhibited a very high CpG methylation level in p16, and ATRA did not influence the promoter methylation of this gene. In the total CCGG sites of the genome, analysed using a methylation-sensitive restriction enzyme, CpG methylation was significantly lower in ATRA-treated HL-60 (p<0.01) and U937 cells (p<0.05) than in controls. Taken together, our findings show that ATRA can influence DNA methylation, and suggest that future research should investigate whether epigenetic modulation may evoke a clinical effect of ATRA in leukemia.
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| 3. |
- Miftakhova, Regina, et al.
(författare)
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Exploring novel therapeutic options in T-LGL, including epigenetic modulation : a case report
- 2010
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Ingår i: Leukemia research. - : Elsevier BV. - 0145-2126 .- 1873-5835. ; 34:7, s. e145-e149
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Tidskriftsartikel (refereegranskat)abstract
- T cell large granular lymphocyte leukemia (T-LGL) is a chronic disease covering a wide spectrum of clinical presentations in the border-land between reactive autoimmunity and overt leukemia [1-2]. Most T-LGL patients follow an indolent course, and display a fairly uniform immunophenotype: TCR alfa/beta+, CD3+, CD4-, CD8+, CD56-, CD57+. This disease often causes significant morbidity mediated by anemia and granulocytopenia, considered to occur by mechanism of T cell cytokines. There is no consensus for optimal therapy of T-LGL, but beneficial effects have been reported for a number of agents including cyclosporin, methotrexate, cyclophosphamide and nucleoside analogs [1-2]. However, to the best of our knowledge, there is no experience with some modalities currently in use for closely related disorders. The purpose of the experiments reported in this case report was to evaluate the need for clinical studies on such therapies, including epigenetic modulation and extracorporeal photopheresis.
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