J Immunol. 2026 Oct 1;215(10):vkag250. doi: 10.1093/jimmun/vkag250.
ABSTRACT
B cell precursor acute lymphoblastic leukemia (BCP ALL) is driven by a combination of genetic alterations that promote invasion and expansion of undifferentiated B cells. Mice that express a NUP98::HOXD13 (NHD13) fusion gene in hematopoietic cells develop a wide range of hematologic malignancy, and when crossed to mice that are prone to develop copy number aberrations (CNA), develop BCP ALL, accompanied by homozygous mutations of Ptpn1. To determine if Ptpn1 deletion can be a causal event leading to BCP-ALL, we crossed NHD13 mice with Ptpn1-/- mice. Mice with NHD13 expression and homozygous Ptpn1 loss developed BCP ALL with a penetrance of 70%, suggesting that Ptpn1 can function as a tumor suppressor gene in this context. Moreover, NHD13/Ptpn1+/- mice that developed BCP ALL typically showed a loss of the Ptpn1 wild type allele in leukemia cells, supporting the assertion that Ptpn1 can function as a tumor suppressor gene. Whole exome sequencing revealed acquired mutations in pathways typically mutated in human BCP ALL, such as B cell differentiation, signal transduction, and cytokine signaling. Transcriptomic analysis indicated -upregulation of signaling pathways in mitochondrial reprogramming and oxidative phosphorylation. In conclusion, we demonstrate the role of Ptpn1 as a tumor suppressor in controlling the development of B cell malignancies.
PMID:42870438 | DOI:10.1093/jimmun/vkag250