Contributions
Abstract: S163
Type: Oral Presentation
Session title: Correlating mutations with phenotype in MDS
Background
In Western world aging-associated bone marrow (BM) dysplasia’s, such as Myeloid Dysplastic Syndrome (MDS), increasingly contribute to anaemia incidence. One major goal of MDS-treatment is to treat anaemia with the aim of avoiding or delaying chronic transfusional support, to decrease the risk of transfusion–related complications and improve quality of life. When serum erythropoietin (EPO) is low, MDS-patients are treated with EPO and/or Sotatercept, displaying a ~50% response rate in terms of erythroid hematological improvement. Anaemia-treatment in MDS therefore urgently requires development of novel options to promote erythropoiesis.
Aims
A fundamental requirement to develop novel treatment opportunities that promote erythropoiesis is to obtain improved understanding of the erythroid homeostatic responses in BM to anaemia.
Methods
We analyzed human healthy and MDS BM by flow cytometry to supplement our exploit of existing genomic and proteomic databases.
Additionally, we performed functional experiments using genomic knockout of our gene of interest, CDH1, using CRISPR-cas9.
Results
We here identify Epithelial cadherin (E-cadherin) to selectively mark the erythroid lineage in human BM. This is striking, because E-cadherin is well-established to mediate epithelial integrity, as key component in adherens junctions. In the epithelium, E-cadherin functions as mechanosensor and transduction cascades, such as the Wnt pathway.
It has been reported that Wnt signaling is aberrantly active in myeloid dysplastic syndrome. We here report our observation that E-cadherin membrane expression is reduced in MDS erythroid progenitors. We hypothesize that consequently, MDS erythroid progenitors lack the gatekeeper function that E-cadherin has on β-catenin signaling.
In our CRISPR-Cas9 KO experiments, we show that E-cadherin in erythroblasts cross talks with the Wnt pathway by stabilizing β-catenin, key Wnt signal transducer, at the cytoplasmic membrane. In addition, we show inhibition of the β-catenin destruction complex results in further accumulation of β-catenin and hampering of erythroid differentiation.
Importantly, we find that E-cadherin expression is not conserved in mouse erythroid progenitors. Erythropoiesis is an evolutionary conserved process and has been extensively studied in vivo using mouse models. Despite many homologies, stress erythropoiesis, the erythroid homeostatic response to anemia, is differently controlled in mice as compared to humans. Stress erythropoiesis in mice is mainly driven extramedullary, in the spleen, and not in BM as seen in humans. The underlying mechanism of stress erythropoiesis in human BM is mostly elusive.
Conclusion
Due its control on cell adhesion, survival and differentiation we hypothesize that E-cadherin in fact may display an unanticipated BM-specific control on (stress) erythropoiesis in human BM that cannot be uncovered by exploring the anemic response in mouse models.
We suggest E-cadherin to function as double edged sword, on the one hand stabilizing, but also sequestering β-catenin at the cytoplasmic membrane. Hereby, E-cadherin links cell adhesion between (pro)erythroblasts in erythroblastic islands with Canonical Wnt signaling.
In extension, we suggest deficient E-cadherin to underlie inefficient stress erythropoiesis and anemia as we observe reduced protein expression in the erythroid lineage in MDS patient BM.
Overall, E-cadherin signaling may underlie (stress) erythropoiesis by controlling differentiation of erythroid progenitors in human BM, and is an interesting candidate for targeted treatment of inefficient erythropoiesis.
Keyword(s):
Abstract: S163
Type: Oral Presentation
Session title: Correlating mutations with phenotype in MDS
Background
In Western world aging-associated bone marrow (BM) dysplasia’s, such as Myeloid Dysplastic Syndrome (MDS), increasingly contribute to anaemia incidence. One major goal of MDS-treatment is to treat anaemia with the aim of avoiding or delaying chronic transfusional support, to decrease the risk of transfusion–related complications and improve quality of life. When serum erythropoietin (EPO) is low, MDS-patients are treated with EPO and/or Sotatercept, displaying a ~50% response rate in terms of erythroid hematological improvement. Anaemia-treatment in MDS therefore urgently requires development of novel options to promote erythropoiesis.
Aims
A fundamental requirement to develop novel treatment opportunities that promote erythropoiesis is to obtain improved understanding of the erythroid homeostatic responses in BM to anaemia.
Methods
We analyzed human healthy and MDS BM by flow cytometry to supplement our exploit of existing genomic and proteomic databases.
Additionally, we performed functional experiments using genomic knockout of our gene of interest, CDH1, using CRISPR-cas9.
Results
We here identify Epithelial cadherin (E-cadherin) to selectively mark the erythroid lineage in human BM. This is striking, because E-cadherin is well-established to mediate epithelial integrity, as key component in adherens junctions. In the epithelium, E-cadherin functions as mechanosensor and transduction cascades, such as the Wnt pathway.
It has been reported that Wnt signaling is aberrantly active in myeloid dysplastic syndrome. We here report our observation that E-cadherin membrane expression is reduced in MDS erythroid progenitors. We hypothesize that consequently, MDS erythroid progenitors lack the gatekeeper function that E-cadherin has on β-catenin signaling.
In our CRISPR-Cas9 KO experiments, we show that E-cadherin in erythroblasts cross talks with the Wnt pathway by stabilizing β-catenin, key Wnt signal transducer, at the cytoplasmic membrane. In addition, we show inhibition of the β-catenin destruction complex results in further accumulation of β-catenin and hampering of erythroid differentiation.
Importantly, we find that E-cadherin expression is not conserved in mouse erythroid progenitors. Erythropoiesis is an evolutionary conserved process and has been extensively studied in vivo using mouse models. Despite many homologies, stress erythropoiesis, the erythroid homeostatic response to anemia, is differently controlled in mice as compared to humans. Stress erythropoiesis in mice is mainly driven extramedullary, in the spleen, and not in BM as seen in humans. The underlying mechanism of stress erythropoiesis in human BM is mostly elusive.
Conclusion
Due its control on cell adhesion, survival and differentiation we hypothesize that E-cadherin in fact may display an unanticipated BM-specific control on (stress) erythropoiesis in human BM that cannot be uncovered by exploring the anemic response in mouse models.
We suggest E-cadherin to function as double edged sword, on the one hand stabilizing, but also sequestering β-catenin at the cytoplasmic membrane. Hereby, E-cadherin links cell adhesion between (pro)erythroblasts in erythroblastic islands with Canonical Wnt signaling.
In extension, we suggest deficient E-cadherin to underlie inefficient stress erythropoiesis and anemia as we observe reduced protein expression in the erythroid lineage in MDS patient BM.
Overall, E-cadherin signaling may underlie (stress) erythropoiesis by controlling differentiation of erythroid progenitors in human BM, and is an interesting candidate for targeted treatment of inefficient erythropoiesis.
Keyword(s):