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TP53 mutations identify a subgroup of AML patients with dramatically impaired outcome
Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.ORCID iD: 0000-0003-4450-0333
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
Division of hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
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2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

TP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of MDM2 (mouse double minute 2), 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. We investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2SNP309 on treatment outcome and overall survival (OS) in 207 Swedish AML patients. We found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with strong association to high risk cytogenetics (p<0.001). TP53mut patients had lower response rates compared to TP53 wild-type (wt) patients (22% and 76% CR, respectively, p<0.001) and reduced OS (5 and 21 months, respectively, p<0.001). In TP53wt patients with abnormal karyotype, the MDM2SNP309 conferred an impaired outcome, with patients carrying the alternative G allele  having shorter OS compared to T/T patients (13 and 29 months, p=0.031). In conclusion, our results show that TP53mut analysis as well as MDM2SNP309 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.

Place, publisher, year, edition, pages
Keyword [en]
AML, TP53, MDM2, SNP309, prognostic markers
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-104948OAI: diva2:700274
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2015-04-14Bibliographically approved
In thesis
1. Molecular genetic studies on Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia - with focus on prognostic markers
Open this publication in new window or tab >>Molecular genetic studies on Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia - with focus on prognostic markers
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The present thesis is focused on the prognostic value of genetic variations and alterations in the initiation and development of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) patients. Several prognostic markers based on genetic or chromosomal aberrations are today used in clinic in these heterogeneous diseases. Novel biomarkers have been identified through next generation sequencing techniques and some of them may be useful as prognostic markers in clinical diagnostic. In papers I-IV we have investigated some of this markers in CLL and AML tumor cells.

In papers I and III we investigated the prognostic value of the MDM2 SNP309 in relation to the presence of TP53 mutations in tumor cells from CLL and AML patients. The SNP309 G-allele was associated with a shorter overall survival in TP53 wildtype CLL and non-normal karyotype AML patients. Mutations in the TP53 gene were found in 6.2% in CLL and 21.7% in AML and were always associated with adverse overall survival. This was most significant observed among the AML patients, where the three year survival was zero.

In paper II we investigated mutations in NOTCH1 and NOTCH2 as prognostic biomarkers in CLL. Notch1 and Notch2 play critical roles in lineage differentiation of white blood cells. We found mutation only in NOTCH1 in a frequency of 6.7% and our analysis revealed a shorter overall survival for these. NOTCH1 mutations were almost mutually exclusive with TP53 mutations and represented together 12.9% in CLL patients, and they may both be strong prognostic biomarkers in CLL.

In paper IV we studied mutations in the tricarboxylic acid cycle. Metabolic disturbances in cancer cells have been known for many years, but recently mechanistic explanations have been identified. Hot spot mutations in IDH1/2 genes, result in neomorphic enzyme activities that results in global hypermethylation of the cancer cell genome. We found mutations in 21% of the AML patients. Among the CN-AML patients there is a lack of prognostic markers and in this subgroup we found patients with IDH2 mutations to have a shorter overall survival (3 vs. 21 months (p=0.009) for mutated and wild-type patients, respectively). Additionally, we also studied a SNP in the IDH1 gene, and both the IDH2 mutations and the SNP showed to have a potential as a new prognostic markers in CN-AML.

In summary, the results in papers I-IV have a potential to function as novel prognostic biomarkers in the clinic for therapeutic considerations and may also be targets for novel drugs for CLL and AML patients.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 59 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1393
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-104951 (URN)10.3384/diss.diva-104951 (DOI)978-91-7519-421-9 (print) (ISBN)
Public defence
2014-03-26, Nils-Holgersalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2015-06-05Bibliographically approved

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Jakobsen Falk, IngridWillander, KerstinChaireti, RozaGréen, HenrikLotfi, KouroshSöderkvist, Peter
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Faculty of Health SciencesDivision of Drug ResearchDivision of Cell BiologyDepartment of HaematologyDivision of Microbiology and Molecular MedicineDepartment of Acute Internal MedicineDepartment of Medical and Health SciencesÖstergötlands Läns LandstingDepartment of Clinical Pathology and Clinical Genetics
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