E-cadherin is a key regulator of epithelial cell–cell adhesion, the loss of which accelerates tumor growth and invasion. E-cadherin is also expressed in hematopoietic cells as well as epithelia. The function of hematopoietic E-cadherin is, however, mostly elusive. In this study, we explored the validity of mouse models to functionally investigate the role of hematopoietic E-cadherin in human hematopoiesis. We generated a hematopoietic-specific E-cadherin knockout mouse model. In mice, hematopoietic E-cadherin is predominantly expressed within the basophil lineage, the expression of which is dispensable for the generation of basophils. However, neither E-cadherin mRNA nor protein were detected in human basophils. In contrast, human hematopoietic E-cadherin marks the erythroid lineage. E-cadherin expression in hematopoiesis thereby revealed striking evolutionary differences between the basophil and erythroid cell lineage in humans and mice. This is remarkable as E-cadherin expression in epithelia is highly conserved among vertebrates including humans and mice. Our study therefore revealed that the mouse does not represent a suitable model to study the function of E-cadherin in human hematopoiesis and an alternative means to study the role of E-cadherin in human erythropoiesis needs to be developed.

Myeloid dysplastic syndrome (MDS) reflects a preleukemic BM disorder with limited treatment options and poor disease survival1. As only a minority of MDS patients is eligible to curative hematopoietic stem cell (HSC) transplantation, there is an urgent need to develop alternative treatment options. Chronic activation of Wnt/β-catenin has been implicated to underlie MDS formation and recently assigned to drive MDS transformation to acute myeloid leukemia (AML). Wnt/β-catenin signaling therefore may harbor a pharmaceutical target to treat MDS and/or prevent leukemia formation. However, targeting the Wnt/β-catenin pathway will also affect healthy hematopoiesis in MDS patients.The control of Wnt/β-catenin on healthy hematopoiesis is poorly understood. Whereas Wnt/β-catenin is dispensable for steady-state erythropoiesis, its activity is essential for stress erythropoiesis in response to BM injury and anemia. Manipulation of Wnt/β-catenin signaling in MDS may therefore deregulate stress erythropoiesis and even increase anemia severity. Here we provide a comprehensive overview of the most recent and established insights in the field to acquire more insight into the control of Wnt/β-catenin signaling on healthy and inefficient erythropoiesis as seen in MDS.

Background:E‐cadherin is well‐established to prevent tumor formation by acting as a master regulator of cell adhesion and growth factor‐mediated survival signaling in epithelial cells. Aside epithelia, E‐cadherin prominently marks malignant erythroid‐marked precursors in bone marrow (BM) of patients with pure erythroid leukemia (PEL) or Myelodysplastic Syndrome (MDS). Yet the function of E‐cadherin on malignant erythroid precursors is largely unknown and questions the role of E‐cadherin in BM during healthy hematopoiesis.Aims:The overall aim of this study is to identify and characterize E‐cadherin expressing hematopoietic cells and to unmask the role of E‐cadherin during hematopoiesis to obtain novel insights into hematopoietic malignancies.Methods:To assess the role of E‐cadherin during hematopoiesis in BM we generated a hematopoietic‐specific E‐cadherin‐knockout mouse model which revealed a significant reduction of splenic erythroid precursors as examined by multi‐color flow cytometry. Moreover we established E‐cadherin to mark a small uncharacterized hematopoietic cell population of short‐lived erythroid/myeloid hematopoietic progenitor cells (HPCs) in healthy BM of adult mouse by performing colony formation and transplantation experiments.Results:Whereas hematopoiesis is commonly viewed and analyzed by well‐defined ‘markers’. HPC's are generally viewed as cKIT‐positive and Lineage (LIN)‐negative. Our data revealed E‐cadherin to mark undefined Ckit‐dim;LIN‐negative short‐lived HPCs, which we combined with our transplantation data identified as ‘late HPCs’. This poorly defined pool of late HPCs is largely understudied mostly because of the lack of specific markers. As we discovered E‐cadherin to mark late HPCs it will also uniquely allow us to interrogate this population to start to understand where late HPCs localize in the BM, how these cells interact with local and stromal cues and how these cells respond during altered hemostatic conditions.Summary/Conclusion:In this study we show that E‐cadherin is expressed in a small subset of hematopoietic bone marrow cells which display myeloid and erythroid progenitor activity. In addition, somatic inactivation of E‐cadherin in mice causes 50% loss of erythropoietic progenitors in the spleen, but not in the BM.Importantly, as E‐cadherin is markedly expressed in MDS, which onset is displayed by inflammation and the formation of anemia, E‐cadherin may herein act as an important regulator directing myelopoieisis over erythropoiesis upon expression on HPCs during inflammation. In fact, epithelial‐expressed E‐cadherin has been well‐established to directly interact with lymphoid effector NK and T‐cells. Hematopoietic‐expressed E‐cadherin on HPCs may therefore also interact with lymphoid effector cells during inflammation to control myelopoiesis over erythropoiesis during inflammation. We therefore currently explore the consequence of hematopoietic‐specific loss of E‐cadherin during Lymphocytic Choriomeningitis Virus (LCMV)‐driven inflammation and anemia formation to assess whether E‐cadherin may in fact act as a critical regulator of HPC differentiation during inflammation, such as displayed during MDS formation.