At the origins of anemia and thrombocytopenia in Fanconi anemia. – FANCDIFF

Fanconi anemia (FA) is a rare bone marrow failure (BMF) syndrome presenting defects in hematopoietic stem and progenitor cells (HSPCs), anemia, thrombocytopenia and increased risk to progress towards myelodysplasia and acute myeloid leukemia.

Even if BMF in FA is thought to be a direct consequence of altered DNA damage responses and associated genetic instability, we currently have a still largely imperfect understanding of the link between the genetic inactivation of a FANC protein, the associated DNA repair alterations and their consequences in term of cellular and clinical outcomes. We have recently described that FANCA mutated cells harbor nucleolar/ribosomal abnormalities impacting translation rate.

We propose that BMF, erythropenia and lthrombocytopenia in FA rely on defects in transcriptome and translatome rather than on altered genetic stability.

Our hypothesis is that alterations of nucleoli, ribosome biogenesis and translation characterized in FANCA deficient patients (70% of FA patients), affect BM
homeostasis and mega- and erythropoiesis, two processes affected by such molecular mechanisms.

To challenge our hypothesis, the project will be separated into 6 packages aiming to :
1- characterize the nucleolar, ribosome activity and mechanisms of translation in hematopoietic cells from Fanca+/+ and Fanca-/- mice in vivo (WP1).
2- characterize the nucleolar, ribosome activity and mechanisms of translation during erythropoiesis in Fanca+/+ and Fanca-/- murine primary cells or cell line in vitro (WP2).
3- characterize the nucleolar and ribosome activity during erythropoiesis in human primary FANCA-proficient and -deficient cell model (WP3).
4- characterize the nucleolar and ribosome activity in megakaryocytes from Fanca+/+ and Fanca-/- murine primary or human CD34+ cells (WP4).
5- characterize the translational activity in terminally differentiated enucleated reticulocytes and platelets from Fanca+/+ and Fanca-/- mice/cells (WP5).
6- test strategies to restore translation deficiencies in FA (WP6).

This knowledge, required to develop new therapeutic approaches to improve FA patient care, will, incidentally, add insights into normal hematopoiesis.
Due to availability of molecules able to modulate mediators associated to nucleolar and ribosomal abnormalities, our observations will open new therapeutic windows to test and support FA patient health.