Erythropoiesis in Healthy and Deregulated Hematopoiesis

Research Lines

Since the start of our group in 2018, we set-up two research lines to improve our insights into red blood cell formation and  deregulation during anemia: “Identification of the role of E-cadherin during hematopoiesis in human bone marrow” and “Genome-wide screening using Crispr-Cas9 to identify novel critical regulators of erythropoiesis”.   

Uncovering the role of E-cadherin in hematopoietic progenitors to improve anaemia in hematopoietic malignancies

Recently we uncovered E-cadherin to critically control the production of human red blood cells. E-cadherin is well established to act as a master regulator of cell junction integrity in epithelia and to act as an important tumor suppressor. Yet, little is known about the role of E-cadherin in healthy hematopoiesis in human bone marrow.

Importantly, increased E-cadherin expression marks erythroid malignancies, characterized by life-threatening anaemia, such as pure erythroid leukemia (PEL) and MDS. Using our state of the art optimized genome editing approach of human-derived hematopoetic stem and progenitor cells we interrogate E-cadherin signalling during erythropoiesis to unravel the control of E-cadherin on the production of red blood cells in healthy and deregulated hematopoiesis.

Research Questions

  • What is the underlying mechanism by which E-cadherin controls the production of Red Blood Cells?
  • Does manipulation of E-cadherin signaling enhance red blood cell formation in anemia-characterised hematopoietic diseases?

Identification of novel genes underlying red blood cell development and hyperplasia formation

TP53 mutations is one of the most recurrent genetic alteration in human cancers. TP53 mutations in acute myeloid leukemia (AML) represent 5–8% of newly diagnosed patients and in 30–40% of those with therapy-related AML. Genetic alterations in TP53 also represents one of the most powerful independent risk factors in AML underscoring the critical tumour suppressive role of p53 in AML.

Whereas loss of p53 instantly drives the formation of acute lymphoid leukemia (ALL), development of AML requires additional epigenetic alterations like constitutively activation of the RAS-ERK pathway. Intriguingly, the erythroid progenitor compartment, has been identified to display the cell of origin of AML formation upon p53 inactivation.

Loss of p53 activity also has been shown to mark an aggressive subtype of erythroid-defined AML and likewise is also detected in erythroid-defined dysplasia’s like myelodysplasia syndrome (MDS). To identify novel genetic aberrations which cooperate with TP53 mutations in erythroid precursor cells that perturb red blood cell formation we recently generated a erythroid precursors cell line harbouring somatic inactivation of TP53 and expression of the RNA-guided Cas9 DNA endonuclease enzyme.

Research Questions

  • What genetic alterations prevent erythroid precursors to mature into RBC and accordingly underlie erythroid differentiation?
  • Do these mutations also define erythroid-defined dysplasia’s and/or leukaemia subtypes?