Polyploidy in health and disease

Testing a new approach to tackle ANRKD26-related thrombocytopenia

Thrombocytopenia is a bleeding disorder caused by a platelet defect. Platelets are generated by megakaryocytes in the bone marrow and enter the circulation to monitor blood vessels and clump in case of a bleeding. Symptoms include increased wound bleeding, which is problematic for injury or surgical procedures also increasing the risk of infections.

 

ANKRD26-related thrombocytopenia is the most common form of inherited platelet disorders and comes with a predisposition to myeloid neoplasms1. Most disease-causing germline mutations are found in the 5’ untranslated region (5’UTR) of ANKRD26 and prevent transcription factor (TF)-mediated downregulation of its expression during megakaryocyte (MK) differentiation. Of note, patient mutations prevent binding of a negative regulator, RUNX1, a key TF controlling blood cell formation. The molecular mechanism(s) how dysregulated ANKRD26 expression impairs platelet formation is not understood.

 

 

 

Here, we are studying whether the disease is related to ANKRD26’s role in centriole biology. ANKRD26 acts as sensor for the excess centrioles and can arrest proliferation of such cells via the PIDDosome and the tumor suppressor p53. As a polyploid cell type, megakaryocytes accumulate centrioles during differentiation. Hence, ANKRD26 downregulation during megakaryopoiesis may enable successful differentiation. In this project, we are using cultured cells and primary patient cells to investigate whether aberrantly high ANKRD26 expression impairs megakaryocyte polyploidization and thus, platelet formation.

This is a Disruptive Innovation Project funded by the ÖAW & FWF (DI_2023-016_SLADKY_ART ATTack)

Team:

Valentina Sladky, PhD (PI)


Raluca-Florina Vintan (MSc Student)