A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis,...

Area of Science:

• Genetics and Molecular Biology
• Hematology
• Oncology

Background:

• The Src family kinase (SFK) member SRC is a key target in cancer drug development due to its frequent activation in various human cancers.
• Deleterious germline mutations in SRC have not been previously reported, making its role in inherited conditions unknown.

Purpose of the Study:

• To identify the genetic basis of a rare bleeding disorder with myelofibrosis.
• To investigate the functional consequences of a newly identified SRC gain-of-function mutation.
• To explore the therapeutic potential of targeting SRC in affected individuals.

Main Methods:

• Genome sequencing and Human Phenotype Ontology (HPO) coding were used to identify the mutation in affected patients.
• In vitro studies using COS-7 cells and patient-derived cells to assess SRC kinase activity and phosphorylation.
• Modeling of the SRC E527K substitution to predict its effect on protein function.
• Zebrafish models were employed to recapitulate the observed human phenotypes.

Main Results:

• A gain-of-function mutation (E527K) in SRC was identified in nine patients, causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies.
• The E527K mutation leads to loss of SRC's self-inhibitory capacity, resulting in increased kinase activity and enhanced tyrosine phosphorylation in platelets and megakaryocytes (MKs).
• Patient-derived MKs exhibit defective proplatelet formation and altered actin organization, phenotypes that can be rescued by SRC kinase inhibition and are recapitulated in zebrafish.

Conclusions:

• The SRC E527K gain-of-function mutation is a novel cause of inherited thrombocytopenia, myelofibrosis, and bleeding disorders.
• Overactive SRC in MKs impairs platelet production and function, offering a new understanding of bleeding complications.
• Targeting SRC kinase activity presents a potential therapeutic strategy for patients with this SRC-related disorder and may inform treatment for cancer patients on SFK inhibitors.