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  • 1.
    Cavelier, Lucia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Häggqvist, Susana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Höijer, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cahill, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Clonal distribution of BCR-ABL1 mutations and splice isoforms by single-molecule long-read RNA sequencing2015In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, article id 45Article in journal (Refereed)
    Abstract [en]

    Background: The evolution of mutations in the BCR-ABL1 fusion gene transcript renders CML patients resistant to tyrosine kinase inhibitor (TKI) based therapy. Thus screening for BCR-ABL1 mutations is recommended particularly in patients experiencing poor response to treatment. Herein we describe a novel approach for the detection and surveillance of BCR-ABL1 mutations in CML patients. Methods: To detect mutations in the BCR-ABL1 transcript we developed an assay based on the Pacific Biosciences (PacBio) sequencing technology, which allows for single-molecule long-read sequencing of BCR-ABL1 fusion transcript molecules. Samples from six patients with poor response to therapy were analyzed both at diagnosis and follow-up. cDNA was generated from total RNA and a 1,6 kb fragment encompassing the BCR-ABL1 transcript was amplified using long range PCR. To estimate the sensitivity of the assay, a serial dilution experiment was performed. Results: Over 10,000 full-length BCR-ABL1 sequences were obtained for all samples studied. Through the serial dilution analysis, mutations in CML patient samples could be detected down to a level of at least 1%. Notably, the assay was determined to be sufficiently sensitive even in patients harboring a low abundance of BCR-ABL1 levels. The PacBio sequencing successfully identified all mutations seen by standard methods. Importantly, we identified several mutations that escaped detection by the clinical routine analysis. Resistance mutations were found in all but one of the patients. Due to the long reads afforded by PacBio sequencing, compound mutations present in the same molecule were readily distinguished from independent alterations arising in different molecules. Moreover, several transcript isoforms of the BCR-ABL1 transcript were identified in two of the CML patients. Finally, our assay allowed for a quick turn around time allowing samples to be reported upon within 2 days. Conclusions: In summary the PacBio sequencing assay can be applied to detect BCR-ABL1 resistance mutations in both diagnostic and follow-up CML patient samples using a simple protocol applicable to routine diagnosis. The method besides its sensitivity, gives a complete view of the clonal distribution of mutations, which is of importance when making therapy decisions.

  • 2.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Wickström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Ekholm, C
    Jenmalm Jensen, A
    Löthgren, A
    Lehmann, F
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Parrow, V
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia2012In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 2, p. e81-Article in journal (Refereed)
    Abstract [en]

    Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nM), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μM). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).

  • 3. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nahi, Hareth
    Palmqvist, Lars
    Paul, Christer
    Paul, Esbjorn
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stockelberg, Dick
    Wei, Yuan
    Green, Henrik
    Lotfi, Kourosh
    Correlation between cytidine deaminase single nucleotide polymorphisms and in vitro drug sensitivity, DNA methylation and outcome in normal karyotype acute myelogenous leukemia2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8Article in journal (Other academic)
  • 4. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Paul, Esbjorn
    Nahi, Hareth
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palmqvist, Lars
    Stockelberg, Dick
    Wei, Yuan
    Green, Henrik
    Lotfi, Kourosh
    Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5 '-nucleotidase2013In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 12, p. 1001-1006Article in journal (Refereed)
    Abstract [en]

    De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A> C rs2072671 and 2451C> T rs532545), 50-nucleotidase (cN-II 7A> G rs10883841), and deoxycytidine kinase (DCK 30UTR 948T> C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and 2451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P< 0.001 and 5 vs. 23 months, P50.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P50.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML. Am. J. Hematol. 88: 1001-1006, 2013.

  • 5. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Paul, Esbjorn
    Nahi, Hareth
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palmqvist, Lars
    Stockelberg, Dick
    Wei, Yuan
    Green, Henrik
    Lotfi, Kourosh
    Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype2014In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 167, no 5, p. 671-680Article in journal (Refereed)
    Abstract [en]

    Drug resistance is a clinically relevant problem in the treatment of acute myeloid leukaemia (AML). We have previously reported a relationship between single nucleotide polymorphisms (SNPs) of ABCB1, encoding the multi-drug transporter P-glycoprotein, and overall survival (OS) in normal karyotype (NK)-AML. Here we extended this material, enabling subgroup analysis based on FLT3 and NPM1 status, to further elucidate the influence of ABCB1 SNPs. De novo NK-AML patients (n = 201) were analysed for 1199G>A, 1236C>T, 2677G>T/A and 3435C>T, and correlations to outcome were investigated. FLT3 wild-type 1236C/C patients have significantly shorter OS compared to patients carrying the variant allele; medians 20 vs. 49 months, respectively, P = 0.017. There was also an inferior outcome in FLT3 wild-type 2677G/G patients compared to patients carrying the variant allele, median OS 20 vs. 35 months, respectively, P = 0.039. This was confirmed in Cox regression analysis. Our results indicate that ABCB1 1236C>T and 2677G>T may be used as prognostic markers to distinguish relatively high risk patients in the intermediate risk FLT3 wild-type group, which may contribute to future individualizing of treatment strategies.

  • 6. Falk, Ingrid Jakobsen
    et al.
    Willander, Kerstin
    Chaireti, Roza
    Lund, Johan
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Green, Henrik
    Soderkvist, Peter
    Lotfi, Kourosh
    TP53 mutations and MDM2 single nucleotide polymorphism 309T-G predicts outcome and treatment resistance in acute myeloid leukemia2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 7. Falk, Ingrid Jakobsen
    et al.
    Willander, Kerstin
    Chaireti, Roza
    Lund, Johan
    Nahi, Hareth
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Green, Henrik
    Lotfi, Kourosh
    Söderkvist, Peter
    TP53 mutations and MDM2(SNP309) identify subgroups of AML patients with impaired outcome2015In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 94, no 4, p. 355-362Article in journal (Refereed)
    Abstract [en]

    BackgroundTP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of mouse double minute 2 (MDM2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. Experimental designWe investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2(SNP309) on treatment outcome and overall survival (OS) in 189 Swedish acute myeloid leukemia patients. The genetic analyses were performed using SSCA and direct sequencing (for mutations in exon 5-8 of TP53) and Pyrosequencing (for the MDM2(SNP309)). ResultsWe found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with association to high-risk cytogenetics (P<0.001). TP53mut patients had lower response rates (22% compared with 76% CR in TP53 wild-type (wt) patients, P<0.001) and reduced OS (2 and 16months, respectively, P<0.001). In TP53wt patients with high or intermediate risk cytogenetic aberrations, the MDM2(SNP309) conferred an impaired outcome, with patients carrying the alternative G-allele having shorter OS compared with T/T patients (median 9 vs. 50months, P=0.020). ConclusionsOur results show that TP53mut analysis and MDM2(SNP309) genotyping may be useful tools for prognostication, risk stratification, and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

  • 8. Lion, T.
    et al.
    Watzinger, F.
    Preuner, S.
    Kreyenberg, H.
    Tilanus, M.
    de Weger, R.
    van Loon, J.
    de Vries, L.
    Cave, H.
    Acquaviva, C.
    Lawler, M.
    Crampe, M.
    Serra, A.
    Saglio, B.
    Colnaghi, F.
    Biondi, A.
    van Dongen, J. J. M.
    van der Burg, M.
    Gonzalez, M.
    Alcoceba, M.
    Barbany, G.
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Roosnek, E.
    Steward, C.
    Harvey, J.
    Frommlet, F.
    Bader, P.
    The EuroChimerism concept for a standardized approach to chimerism analysis after allogeneic stem cell transplantation2012In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, no 8, p. 1821-1828Article in journal (Refereed)
    Abstract [en]

    Hematopoietic stem cell transplantation is becoming an increasingly important approach to treatment of different malignant and non-malignant disorders. There is thus growing demand for diagnostic assays permitting the surveillance of donor/recipient chimerism posttransplant. Current techniques are heterogeneous, rendering uniform evaluation and comparison of diagnostic results between centers difficult. Leading laboratories from 10 European countries have therefore performed a collaborative study supported by a European grant, the EuroChimerism Concerted Action, with the aim to develop a standardized diagnostic methodology for the detection and monitoring of chimerism in patients undergoing allogeneic stem cell transplantation. Following extensive analysis of a large set of microsatellite/short tandem repeat (STR) loci, the EuroChimerism (EUC) panel comprising 13 STR markers was established with the aim to optimally meet the specific requirements of quantitative chimerism analysis. Based on highly stringent selection criteria, the EUC panel provides multiple informative markers in any transplant setting. The standardized STR-PCR tests permit detection of donor-or recipient-derived cells at a sensitivity ranging between 0.8 and 1.6%. Moreover, the EUC assay facilitates accurate and reproducible quantification of donor and recipient hematopoietic cells. Wide use of the European-harmonized protocol for chimerism analysis presented will provide a basis for optimal diagnostic support and timely treatment decisions.

  • 9.
    Lotfi, Kourosh
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Mosrati, Mohamed Ali
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Willander, Kerstin
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.;Linkoping Univ, Dept Haematol, Linkoping, Sweden..
    Falk, Ingrid Jakobsen
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stockelberg, Dick
    Sahlgrens Univ Hosp, Dept Internal Med, Sect Hematol & Coagulat, Gothenburg, Sweden..
    Wei, Yuan
    Sahlgrens Univ Hosp, Dept Internal Med, Sect Hematol & Coagulat, Gothenburg, Sweden..
    Soderkvist, Peter
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Association of TERT polymorphism with acute myeloid leukemia risk and prognosis2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75Article in journal (Other academic)
  • 10.
    Löf, Liza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arngården, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Siart, Benjamin
    Jansson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlin, Joakim S
    Thörn, Ingrid
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Christiansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hermansson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ahlstrand, Erik
    Wålinder, Göran
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rosenquist, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Landegren, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Flow Cytometric Measurement of Blood Cells with BCR-ABL1 Fusion Protein in Chronic Myeloid Leukemia2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, p. 1-9, article id 623Article in journal (Refereed)
    Abstract [en]

    Chronic myeloid leukemia (CML) is characterized in the majority of cases by a t(9;22)(q34;q11) translocation, also called the Philadelphia chromosome, giving rise to the BCR-ABL1 fusion protein. Current treatment with tyrosine kinase inhibitors is directed against the constitutively active ABL1 domain of the fusion protein, and minimal residual disease (MRD) after therapy is monitored by real-time quantitative PCR (RQ-PCR) of the fusion transcript. Here, we describe a novel approach to detect and enumerate cells positive for the BCR-ABL1 fusion protein by combining the in situ proximity ligation assay with flow cytometry as readout (PLA-flow). By targeting of the BCR and ABL1 parts of the fusion protein with one antibody each, and creating strong fluorescent signals through rolling circle amplification, PLA-flow allowed sensitive detection of cells positive for the BCR-ABL1 fusion at frequencies as low as one in 10,000. Importantly, the flow cytometric results correlated strongly to those of RQ-PCR, both in diagnostic testing and for MRD measurements over time. In summary, we believe this flow cytometry-based method can serve as an attractive approach for routine measurement of cells harboring BCR-ABL1 fusions, also allowing simultaneously assessment of other cell surface markers as well as sensitive longitudinal follow-up.

  • 11.
    Mosrati, Mohamed Ali
    et al.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Willander, Kerstin
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.;Linkoping Univ, Dept Haematol, Linkoping, Sweden..
    Falk, Ingrid Jakobsen
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stockelberg, Dick
    Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Dept Internal Med, Gothenburg, Sweden..
    Wei, Yuan
    Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Dept Internal Med, Gothenburg, Sweden..
    Lotfi, Kourosh
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.;Cty Council Ostergotland, Dept Hematol, Linkoping, Sweden..
    Soderkvist, Peter
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Association between TERT promoter polymorphisms and acute myeloid leukemia risk and prognosis2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 28, p. 25109-25120Article in journal (Refereed)
    Abstract [en]

    Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNVs in 226 acute myeloid leukemia (AML) patients and 806 healthy individuals in a case referent design, where also overall survival was assessed. A significant association for increased risk of AML was found for TERT SNVs, rs2853669 (OR = 2.45, p = 0.00015) and rs2736100 (OR = 1.5, p = 0.03). The overall survival for patients with CC genotype of rs2853669 was significantly shorter compared to those with TT or TC genotypes (p = 0.036 and 0.029 respectively). The influence of TERT rs2853669 CC on survival was confirmed in multivariable Cox regression analysis as an independent risk biomarker in addition to high risk group, higher age and treatment. No hot spot TERT promoter mutations at -228C>T or -250C>T or POT1 mutations could be identified in this AML cohort. We show that rs2853669 CC may be a risk factor for the development of AML that may also be used as a prognostic marker to identify high risk normal karyotype -AML (NK-AML) patients, for treatment guidance.

  • 12.
    Pfeifer, H.
    et al.
    Goethe Univ, Dept Med, Hematol Oncol, Frankfurt, Germany.
    Cazzaniga, G.
    Univ Milano Bicocca, San Gerardo Hosp, Pediat Clin, Monza, Italy.
    van der Velden, V. H. J.
    Erasmus MC, Dept Immunol, Med Ctr Rotterdam, Rotterdam, Netherlands.
    Cayuele, J. M.
    Univ Paris Diderot, Univ Hosp St Louis, Hematol Lab, Paris, France;Univ Paris Diderot, Univ Hosp St Louis, EA3518, Paris, France.
    Schafer, B.
    Kinderspital Zurich, Onkol Diagnost Lab, Zurich, Switzerland.
    Spinelli, O.
    ASST Papa Giovanni XXIII, Hematol & Bone Marrow Transplant Unit, Bergamo, Italy.
    Akiki, S.
    Birmingham Womens NHS Fdn Trust, Reg Genet Lab, Birmingham, W Midlands, England.
    Avigad, S.
    Schneider Childrens Med Ctr Israel, Pediat Hematol Oncol, Petah Tiqwa, Israel.
    Bendit, I
    Univ Sao Paulo, Med Sch, Div Hematol & Hemotherapy, Sao Paulo, Brazil.
    Borg, K.
    Inst Hematol & Transfus Med, Dept Diagnost Hematol, Warsaw, Poland.
    Cave, H.
    Hop Robert Debre, Dept Genet Biochem, Paris, France.
    Elia, L.
    Univ Roma La Sapienza, Dept Hematol, Lab Mol Biol, Rome, Italy.
    Reshmi, S. C.
    Nationwide Childrens Hosp, Inst Genom Med, Columbus, OH USA;Ohio State Univ, Columbus, OH USA.
    Gerrard, G.
    Imperial Coll London, Ctr Hematol, Imperial Mol Pathol, London, England.
    Hayette, S.
    Hosp Civils Lyon, Ctr Hosp Lyon Sud, Lab Mol Biol, Lyon, France;Hosp Civils Lyon, Ctr Hosp Lyon Sud, UMR5239, Lyon, France.
    Hermansson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Juh, A.
    Natl Univ Singapore Hosp, Dept Pediat, Div Pediat Hematol Oncol, Singapore, Singapore.
    Jurcek, T.
    Masaryk Univ, Dept Internal Med Hematol & Oncol, Brno, Czech Republic;Univ Hosp Brno, Brno, Czech Republic.
    Chillon, M. C.
    Salamanca Univ, CSIC, Univ Hosp Salamanca IBSAL, Dept Hematol, Salamanca, Spain;Salamanca Univ, Canc Res Ctr, IBMCC, CSIC, Salamanca, Spain.
    Homburg, C.
    Sanquin Diagnost, Dept Expt Immunhematol Immuncytol, Amsterdam, Netherlands.
    Martinelli, G.
    Univ Bologna, Dept Expt Diagnost & Specialty Med, Bologna, Italy.
    Kairisto, V
    Turku Univ Hosp, TYKSLAB, Lab Mol Genet, Turku, Finland.
    Langen, T.
    Univ Leipzig, Abt Hamatol & Internist Onkol, Leipzig, Germany.
    Lion, T.
    Labdia Labordiagnost & Med Univ, Childrens Canc Res Inst, Vienna, Austria.
    Mueller, M. C.
    Med Univ Heidelberg, Med Klin 3, Fak Mannheim, Mannheim, Germany.
    Pane, F.
    Azienda Osped Univ Federico II Napoli Univ, Naples, Italy.
    Rai, L.
    UCL, Dept Hematol, Royal Free Campus, London, England.
    Damm-Welk, C.
    Justus Liebig Univ Giessen, Univ Hosp, Dept Pediat Hematol & Oncol, Giessen, Germany.
    Sacha, T.
    Jagiellonain Univ Krakow, Hematol Dept, Krakow, Poland.
    Schnittger, S.
    MLL, Max Lebsche Pl 31, Munich, Germany.
    Touloumenidou, T.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.
    Valerhaugen, H.
    Oslo Univ Hosp, Norwegian Radium Hosp, Dept Pathol, Oslo, Norway.
    Vandenberghe, P.
    Univ Hosp Leuven, Ctr Human Genet, Leuven, Belgium;Katholieke Univ Leuven, Leuven, Belgium.
    Zuna, J.
    Charles Univ Prague, CLIP, Dept Paediat Haematol & Oncol, Fac Med 2, Prague, Czech Republic;UH Motol, Prague, Czech Republic.
    Server, H.
    Goethe Univ, Dept Med, Hematol Oncol, Frankfurt, Germany.
    Herrmann, E.
    Goethe Univ, Inst Biostat & Math Modellierung, Frankfurt, Germany.
    Markovic, S.
    Goethe Univ, Dept Med, Hematol Oncol, Frankfurt, Germany.
    van Dongen, J. J. M.
    Erasmus MC, Dept Immunol, Med Ctr Rotterdam, Rotterdam, Netherlands;Leiden Univ, Dept Immunohematol & Blood Transfus, Med Ctr, Leiden, Netherlands.
    Ottmann, O. G.
    Cardiff Univ, Sch Med, Div Canc & Hematol, Cardiff, S Glam, Wales.
    Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph plus ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL12019In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 8, p. 1910-1922Article in journal (Refereed)
    Abstract [en]

    Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10(-3) and 36/67 (53%) and 53/67 (79%) at 10(-4)BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

  • 13.
    Åleskog, Anna
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Höglund, Martin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Pettersson, Jenny
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Hermansson, Monica
    Department of Genetics and Pathology.
    Larsson, Rolf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lindhagen, Elin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    In vitro activity of the flt3-inhibitor su5614 and standard cytotoxic agents in tumour cells from patients with wild type and mutated flt3 acute myeloid leukaemia.2005In: Leuk Res, ISSN 0145-2126, Vol. 29, no 9, p. 1079-81Article in journal (Refereed)
1 - 13 of 13
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