Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis

Abstract

Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Though numerous precipitating etiologies have been identified, the reason that HLH only occurs in a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, is delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) display an exaggerated response to TLR9 agonism including worse splenomegaly and anemia. Our data suggests that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease.

Clonal hematopoiesis in patients receiving chimeric antigen receptor T-cell therapy

“…9,10 These alterations likely have a broader impact on human disease, including in states of hyperinflammation, response to immune-targeting therapies, or other autoimmune diseases. 11,14,15 Mutations that are present in the CAR T-cell product itself, particularly in TET2 and DNMT3A, can alter T-cell programs and the activity of CAR T-cells. 12,13,19,20 Our data support the idea that clonal hematopoietic mutations in blood cells can influence inflammatory pathways through diverse mechanisms and across numerous disease and therapeutic contexts.…”

“…CHIP mutations in myeloid cells have been shown to enhance inflammatory signaling, including via interleukin-6 (IL-6), a key mediator of CRS, and alter interactions between innate and adaptive immune cells. [8][9][10][11] Moreover, DNMT3A and TET2, genes commonly mutated in CHIP, have been shown to influence CAR T-cell programs. 12,13 We therefore sought to understand the frequency and clinical consequences of CH in a cohort of patients receiving CAR T-cell therapy.…”

Clonal hematopoiesis and its emerging effects on cellular therapies

“…Second, CH enhances the risk of inflammatory diseases like cardiovascular disease (CVD) [7,18,55,56] and adult onset autoinflammatory disease [57]. CH patients are described to be enriched in illnesses like hemophagocytic lymphohistiocytosis [58], severe COVID-19 [59], anti-neutrophil antibody-associated vasculitis [60], to name a few examples of the expanding list. Third, cytostatic therapy, but not immune checkpoint blockade, is a major risk factor for development of CH and shapes the mutational spectrum [15,[61][62][63].…”

Germline risk of clonal haematopoiesis

“…There is accumulating evidence that CHIP mutations may interact with human illnesses beyond cancer and CVD. Somatic CHIP mutations have been associated with several diseases in which inflammation features prominently, including chronic obstructive pulmonary disease 18 , 62 , adult-onset haemophagocytic lymphohistiocytosis 63 and anti-neutrophil cytoplasmic antibody-associated vasculitis 64 . CHIP also appears to be associated with several types of infections and with potentially severe disease manifestations among those infected with SARS-CoV-2 (ref.…”