IL-6 Monoclonal Antibody Elsilimomab Inhibits Bone Marrow Stromal Cell Senescence Induced by Dnmt3a-Mutant Clonal Hematopoiesis

David Bernal

Document Type

Article

Publication Date

Summer 2023

Keywords

JMG

JAX Location

In: Student Reports, Summer 2023, The Jackson Laboratory

Abstract

Due to the long-lived naure of adult stem cells, somatic DNA mutations accumulate with each cell division. In the hematopoietic system, an accumulation of these somatic mutations and competitive pressures provides a selective advantage to mutated hematopoietic stem and progenitor cells (HSPCs), leading to a 'clone' of cells carrying the same somatic mutation(s). THis is called clonal hematopoiesis (CH) and is associated with increased risk of developing blood cancers including acute myeloid leukemia (AML). The most prominent mutation found in CH and AML is in the gene DNA methyltransferase 3a (Dnmt3a). Our lab has recently discovered that, in addition to there being an expanded clone of hematopoietic stem progenitor cells in clonal hematopoiesis, these cells also abnormally produce and release certain secreted factors and inflammatory cytokines that cause a senescence phenotye in bone marrow stromal cells (BMSC), which may contribute to the development of blood cancers. Based on preliminary data that Dnmt3a-mutant HSPCs produce and secrete interleukin-6 (IL-6), and published literature that IL-6 can induce senescence of BMSCs, I propose to test the hypothesis that IL-6 produced by Dnmt3a-mutant HSPCs induces BMSC senescence. To test this hypothesis, I have used an inhibitor of IL-6 (Elsilimomab) and have evaluated its effect on BMSC senescence phenotypes. The data I have generated supports that inhibition of by Elsilimomab results in reduction of Dnmt3a-Mutant HSPC-induced BMSC senescence.

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