TY  - JOUR
A1  - Haertle, Larissa
A1  - El Hajj, Nady
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Nanda, Indrajit
A1  - Lehnen, Harald
A1  - Haaf, Thomas
T1  - Epigenetic signatures of gestational diabetes mellitus on cord blood methylation
JF  - Clinical Epigenetics
N2  - Background:
Intrauterine exposure to gestational diabetes mellitus (GDM) confers a lifelong increased risk for metabolic and other complex disorders to the offspring. GDM-induced epigenetic modifications modulating gene regulation and persisting into later life are generally assumed to mediate these elevated disease susceptibilities. To identify candidate genes for fetal programming, we compared genome-wide methylation patterns of fetal cord bloods (FCBs) from GDM and control pregnancies.

Methods and results:
Using Illumina’s 450K methylation arrays and following correction for multiple testing, 65 CpG sites (52 associated with genes) displayed significant methylation differences between GDM and control samples. Four candidate genes, ATP5A1, MFAP4, PRKCH, and SLC17A4, from our methylation screen and one, HIF3A, from the literature were validated by bisulfite pyrosequencing. The effects remained significant after adjustment for the confounding factors maternal BMI, gestational week, and fetal sex in a multivariate regression model. In general, GDM effects on FCB methylation were more pronounced in women with insulin-dependent GDM who had a more severe metabolic phenotype than women with dietetically treated GDM.

Conclusions:
Our study supports an association between maternal GDM and the epigenetic status of the exposed offspring. Consistent with a multifactorial disease model, the observed FCB methylation changes are of small effect size but affect multiple genes/loci. The identified genes are primary candidates for transmitting GDM effects to the next generation. They also may provide useful biomarkers for the diagnosis, prognosis, and treatment of adverse prenatal exposures.
KW  - fetal programming
KW  - insulin treatment
KW  - DNA methylation
KW  - fetal cord blood
KW  - gestational diabetes mellitus
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159459
VL  - 9
IS  - 28
ER  - 
TY  - JOUR
A1  - Garitano-Trojaola, Andoni
A1  - Sancho, Ana
A1  - Götz, Ralph
A1  - Eiring, Patrick
A1  - Walz, Susanne
A1  - Jetani, Hardikkumar
A1  - Gil-Pulido, Jesus
A1  - Da Via, Matteo Claudio
A1  - Teufel, Eva
A1  - Rhodes, Nadine
A1  - Haertle, Larissa
A1  - Arellano-Viera, Estibaliz
A1  - Tibes, Raoul
A1  - Rosenwald, Andreas
A1  - Rasche, Leo
A1  - Hudecek, Michael
A1  - Sauer, Markus
A1  - Groll, Jürgen
A1  - Einsele, Hermann
A1  - Kraus, Sabrina
A1  - Kortüm, Martin K.
T1  - Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia
JF  - Communications Biology
N2  - The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD+AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD+AML. Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatment approach for FLT3 mutant AML.
KW  - actin
KW  - acute myeloid leukaemia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260709
VL  - 4
IS  - 1
ER  -