Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated...

Area of Science:

• Hematology
• Molecular Biology
• Genetics

Background:

• SLFN14-related thrombocytopenia is a rare bleeding disorder linked to SLFN14 mutations.
• SLFN14 is expressed in megakaryocytes (MKs) and erythroblasts, but its role in megakaryopoiesis and platelet function is unknown.
• Understanding SLFN14's function is key to explaining bleeding phenotypes in patients.

Purpose of the Study:

• To investigate the role of SLFN14 in megakaryopoiesis and platelet function.
• To elucidate the molecular mechanisms underlying SLFN14 deficiency-related bleeding disorders.
• To establish a murine model for studying SLFN14's function in vivo.

Main Methods:

• Generated a novel murine model with platelet and MK-specific SLFN14 deletion (Slfn14;PF4-Cre).
• Assessed platelet function, bleeding tendency, and thrombus formation using intravital imaging.
• Performed RNA sequencing and gene ontology analysis on MKs and platelets.

Main Results:

• SLFN14-deficient platelets showed reduced signaling to thrombin and impaired thrombin formation.
• Mice exhibited increased bleeding tendency and delayed thrombus formation.
• Reduced MK numbers in bone marrow and altered ubiquitination, ATP activity, and cytoskeleton pathways were observed.

Conclusions:

• SLFN14 deletion in MKs and platelets leads to significant platelet dysfunction.
• Altered transcriptomes in MKs and platelets explain the observed platelet dysfunction and bleeding phenotype.
• This study clarifies the molecular basis of SLFN14 mutations causing bleeding disorders in humans and mice.