26 research outputs found
Prognostic and biological implications of epigenetic changes in leukemia
The field of epigenetic research in hematology and oncology is rapidly expanding.
Even so, reliable data linking epigenetic changes to clinical outcomes are scarce. We
conducted two retrospective studies in AML. The first (paper I) was performed in 107
AML patients without a previous history of MDS where we approximated the global
DNA 5-methylcytosine content with a methylation sensitive restriction enzyme assay,
the promoter DNA methylation status of three known tumor suppressor genes,
CDKN2B (p15), HIC1 and CDH1, and in a subset of 20 patients genome-wide
promoter methylation by the Illumina HumanMethylation27 array. Promoter
methylation of CDKN2B was common (66%), and associated with better overall and
disease free survival in uni- and multivariate analysis. Average genome wide promoter
methylation levels were also associated with overall and disease free survival and
correlated inversely with global 5-methylcytosine content, which in turn associated
with response to induction therapy. The second study (paper II) was restricted to
cytogenetically normal de-novo AML cases. In a test group of 58 samples we
investigated genome wide promoter methylation by the Illumina HumanMethylation27
array and correlated the methylation patterns with the mutational status of NPM1,
FLT3, CEBPA, IDH1, IDH2, DNMT3A and clinical parameters. We found increased
promoter methylation in NPM1 and IDH mutated samples with specific methylation
patterns for these two mutations. Compared with a control group of normal myeloid
progenitor cells from 9 donors the most differentially methylated genes in AML were
those that in previous studies were targeted by Polycomb group proteins in embryonic
tissue. Furthermore, we found that the methylation levels of the Polycomb targeted
genes were associated with overall and progression free survival. The prognostic
association was confirmed in a validation cohort of 60 patients and retained
significance in multivariate analysis. The third study of this thesis (paper III) was
designed to search for the second tumor suppressor gene commonly thought to reside
on chromosome 11q21-23 in CLL, based on the finding of two microdeletions in a
previous study. Through DNA methylation screening we found a 48% prevalence of
aberrant promoter methylation of the shared two-directional promoter of BTG4 /
microRNA-34b/c. Functional studies with stress incubation of primary CLL samples as
well as the HG3 cell line showed an selective up-regulation of miR-34b/c transcripts in
unmethylated cells, but no induction of BTG4 regardless of methylation status.
Chromatin immunoprecipitation experiments showed the presence of repressive
chromatin marks in both CLL and normal lymphocytes, which may explain our
observation that the basal expression levels of miR-34b/c were low both in normal
lymphocytes and CLL cells regardless of methylation status, compatible with a
âepigenetic switchâ from conditional to permanent silencing in methylated samples.
We conclude that DNA methylation patterns are associated with mutational status and
clinical outcomes in AML. Furthermore we believe that miR-34b/c may function as a
tumor suppressor gene in CLL, incapacitated by an epigenetic switch mechanism in
approximately 50% of CLL samples
Molecular status 36 months after TKI discontinuation in CML is highly predictive for subsequent loss of MMR-final report from AFTER-SKI
Non peer reviewe
The prognostic impact of FLT3-ITD and NPM1 mutation in adult AML is age-dependent in the population-based setting
In acute myeloid leukemia (AML) FLT3 internal tandem duplication (ITD) and nucleophosmin 1 (NPM1) mutations provide prognostic information with clinical relevance through choice of treatment, but the effect of age and sex on these molecular markers has not been evaluated. The Swedish AML Registry contains data on FLT3-ITD and NPM1 mutations dating to 2007, and 1570 adult patients younger than 75 years, excluding acute promyelocytic leukemia, had molecular results reported. Females more often had FLT3ITD and/or NPM1mut (FLT3ITD: female, 29%; male, 22% [P = .0015]; NPM1mut: female, 36%; male, 27% [P = .0001]), and more males were double negative (female, 53%; male, 64%; P < .0001). Patients with FLT3ITD were younger than those without (59 vs 62 years; P = .023), in contrast to patients with NPM1mut (62 vs 60 years; P = .059). Interestingly, their prognostic effect had a strong dependence on age: FLT3ITD indicated poor survival in younger patients (<60 years; P = .00003), but had no effect in older patients (60-74 years; P = .5), whereas NPM1mut indicated better survival in older patients (P = .00002), but not in younger patients (P = .95). In FLT3ITD/NPM1mut patients, the survival was less dependent on age than in the other molecular subsets. These findings are likely to have clinical relevance for risk grouping, study design, and choice of therapy
Incidence and prognostic significance of isolated trisomies in adult acute myeloid leukemia : A population-based study from the Swedish AML registry
OBJECTIVES AND METHODS: To ascertain the incidence/clinical implications of isolated autosomal trisomies in adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry.RESULTS: Of the 3179 cytogenetically informative AMLs diagnosed January 1997-May 2015, 246 (7.7%) had isolated trisomies. The frequency increased by age (2.4% at age 18-60 years vs. 23% at >60 years; P<.0001); the median age was 69 years. The five most common were +8 (4.0%), +13 (0.9%), +11 (0.8%), +21 (0.7%), and +4 (0.5%). Age and gender, types of AML and treatment, and complete remission and early death rates did not differ between the single trisomy and the intermediate risk (IR) groups or among cases with isolated gains of chromosomes 4, 8, 11, 13, or 21. The overall survival (OS) was similar in the single trisomy (median 1.6 years) and IR groups (1.7 years; P=.251). The OS differed among the most frequent isolated trisomies; the median OS was 2.5 years for +4, 1.9 years for +21, 1.5 years for +8, 1.1 years for +11, and 0.8 years for +13 (P=.013).CONCLUSION: AML with single trisomies, with the exception of +13, should be grouped as IR