Altered PTPN13-β-catenin interaction by pathogenic mutations and involvement of this axis in B-cell receptor...

Protein tyrosine phosphatase non-receptor type 13 (PTPN13) is a non-receptor protein tyrosine phosphatase with context-dependent roles as tumour suppressor or promoter. Its modular structure supports multiple molecular interactions, including a critical one with β-catenin, a regulator of the haematopoietic system. We previously identified three pathogenic PTPN13 mutations in families with acute lymphoblastic leukaemia (ALL), anaemia, and/or inherited bone marrow failure (IBMF). Our current findings reveal that these mutations impair the PTPN13-β-catenin interaction. β-catenin and PTPN13 are stabilised upon B-cell receptor (BCR) activation, while PTPN13 silencing reduces Bruton's tyrosine kinase (BTK) activation and β-catenin levels, indicating that PTPN13 modulates BCR signalling at multiple points. Together with prior evidence showing that PTPN13 mutations compromise protein stability and decrease β-catenin levels, these data support a role for disrupted lymphoid signalling. Altered expression of key surface markers (CD25 and CD38) upon silencing of either PTPN13 or β-catenin further supports this interpretation. In conclusion, our study identifies the PTPN13-β-catenin axis as a critical regulator of lymphoid cell homeostasis and highlights its disruption as a potential driver of haematological abnormalities in patients carrying PTPN13 mutations.