NU 2016-012
INVENTORS
SHORT DESCRIPTION
Methods of targeting CD40L for treating TET2-mutant pre-malignant myeloid conditions
BACKGROUND
TET2 is one of the most frequently mutated genes in myeloid neoplasms and their precursor conditions, such as clonal hematopoiesis of indeterminate potential (CHIP), clonal cytopenia of undetermined significance (CCUS), and myelodysplastic syndrome (MDS). TET2 mutations trigger chronic bone marrow inflammation and dysregulated innate immune signaling, which fosters clonal expansion of mutant hematopoietic stem cells and induces a maladaptive remodeling of the immune system, characterized by a pathogenic crosstalk between the bone marrow stroma and adaptive immune cells that facilitates disease progression. Current clinical management largely relies on non-specific cytotoxic therapies or supportive care, which are often associated with significant systemic toxicity and fail to target the underlying mutation-specific inflammatory mechanisms that drive clonal evolution.
ABSTRACT
This therapeutic approach targets CD40L to treat TET2-mutant pre-malignant myeloid conditions by disrupting a pathogenic feedback loop between the bone marrow stroma and the immune system discovered by Northwestern inventors. The method employs CD40L inhibitors to block interactions between antigen-presenting macrophages and T follicular helper-like CD4+ T cells that are activated by gasdermin D-mediated stromal pyroptosis. Technically, this intervention suppresses the clonal expansion of Tet2-deficient hematopoietic stem and progenitor cells, reduces inflammatory monocytosis, and reverses maladaptive tissue remodeling in the bone marrow and spleen.
APPLICATIONS
ADVANTAGES
IP STATUS
PUBLICATIONS