PS1230 DEFINING THE ROLE OF E‐CADHERIN DURING HEALTHY AND MALIGNANT HEMATOPOIESIS
Authors: Krimpenfort R. , Nethe M. 
Published: June 2019

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.