Surficial geologic map of the Des Moines Lobe of Iowa, Phase 5: Polk County

https://ir.uiowa.edu/igs_ofm/1030/thumbnail.jp

Association between DNMT3A Mutations and Prognosis of Adults with <i>De Novo</i> Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

<div><p>Background</p><p>DNA methyltransferase 3A (DNMT3A) mutations were considered to be independently associated with unfavorable prognosis in adults with de novo acute myeloid leukemia (AML), however, there are still debates on this topic. Here, we aim to further investigate the association between DNMT3A mutations and prognosis of patients with AML.</p> <p>Methods</p><p>Eligible studies were identified from several data bases including PubMed, Embase, Web of Science, ClinicalTrials and the Cochrane Library (up to June 2013). The primary endpoint was overall survival (OS), while relapse-free survival (RFS) and event-free survival (EFS) were chosen as secondary endpoints. If possible, we would pool estimate effects (hazard ratio [HR] with 95% confidence interval[CI]) of outcomes in random and fixed effects models respectively.</p> <p>Results</p><p>That twelve cohort studies with 6377 patients exploring the potential significance of DNMT3A mutations on prognosis were included. Patients with DNMT3A mutations had slightly shorter OS (HR = 1.60; 95% CI, 1.31–1.95; P<0.001), as compared to wild-type carriers. Among the patients younger than 60 years of age, DNMT3A mutations predicted a worse OS (HR = 1.84; 95% CI, 1.36–2.50; P<0.001). In addition, mutant DNMT3A predicted inferior OS (HR = 2.30; 95% CI, 1.78–2.97; P = 0.862) in patients with unfavorable genotype abnormalities. Similar results were also found in some other subgroups. However, no significant prognostic value was found on OS (HR = 1.40; 95% CI, 0.98–1.99; P = 0.798) in the favorable genotype subgroup. Similar results were found on RFS and EFS under different conditions.</p> <p>Conclusions</p><p>DNMT3A mutations have slightly but significantly poor prognostic impact on OS, RFS and EFS of adults with de novo AML in total population and some specific subgroups.</p> </div

Outcome of subgroups in a random effects model.

<p>N.of S., number of studies;</p><p>D+/−, indicates ratio of number of patients with mutant DNMT3A to patients with wild-type DNMT3A;</p><p>—, reflects there is no corresponding data presented; Abbreviations: mt, mutation; wt, wild type.</p

Confunnel with filled studies from metatrim:

<p>mutant DNMT3A versus wild-type DNMT3A in a random effects model. The pooled HR on overall survival from 12 published studies is robust and the heterogeneity mainly results from unpublished studies.</p

Forest plot of the HRs for relapse-free or event-free survival of AML patients.

<p>DNMT3A mutations versus wild-type DNMT3A. I–V Subtotal represented the pooled HRs with 95% CIs using a fixed effects model; D+L Subtotal represented the pooled HR with 95% CI using a random effects model.</p

PRISMA flow diagram for study review and inclusion.

<p>PRISMA flow diagram for study review and inclusion.</p

Forest plot of the HR for overall survival of all AML patients.

<p>DNMT3A mutations versus wild-type DNMT3A. I–V Overall: the pooled HR with 95% CI using a fixed effects model; D+L Overall: the pooled HR with 95% CI using a random effects model.</p

Outcome of subgroups in a fixed effects model.

<p>N.of S., number of studies;</p><p>D+/−, indicates ratio of number of patients with mutant DNMT3A to patients with wild-type DNMT3A;</p><p>—, reflects there is no corresponding data presented; Abbreviations: mt, mutation; wt, wild type.</p

Funnel plots illustrated significant asymmetry on HR for overall survival of all patients.

<p>Studies were distributed asymmetrically and suggested biases exist.</p

Kinetic expression of the hematopoietic and pluripotent genes during hBMMSC-iPSC commitment to CD34+ progenitor cells, and then to hematopoietic cells.

<p>(A-D) Kinetic expression of CD34+ and CD45+ during the hematopoietic cell differentiation of hBMMSC-iPSCs with flow cytometry analysis. Undifferentiated hBMMSC-iPSCs expressed no CD34 or CD45 (A). After treatment with the cocktail containing mesodermal, hematopoietic, and endothelial inducers for 5 days, hBMMSC-iPSCs expressed about 5% percentage of CD34+ but few CD45+ cells (B). After culturing with the following hematopoietic and endothelial inducer cocktail for additional 7–9 days, the proportion of CD34+ population increased to nearly 20% and a few CD45+ cells were obtained at this stage (C). In hematopoietic potential assay of CD34+ progenitor cells, about 5% population of CD34+CD45+ cells were developed from the CFU assay, and the percentage of CD45+ cells increased to about 25% during the differentiation culture (D). (E-F) Dynamically relative expression of the pluripotent marker Oct4 and the hematopoietic cell markers TAL-1, SCL during hBMMSC-iPSC commitment to CD34+ progenitor cells, and then to hematopoietic cells by RT-PCR (E) and fluorescence intensity (F) assay in the differentiation culture. The values were the mean ± SD of 3 independent experiments. (G) Kinetics of CD34+ cells during hematopoietic differentiation of hBMMSC-iPSCs versus hFib-iPSCs treated with the inducers.</p