Diffuse Large B Cell Lymphoma in Hyper-IgE Syndrome Due To STAT3 Mutation

Abstract

The Job or hyper-immunoglobulinemia E syndrome is a primary immunodeficiency that is usually inherited in an autosomal dominant fashion. With the discovery of mutations in the STAT3 gene in the majority of autosomal dominant cases, it is now possible to make a molecular diagnosis of hyper-IgE syndrome. Both primary and secondary immunodeficiencies, including hyper-IgE syndrome, may predispose for malignancies, especially lymphomas, mainly mature B cell lymphomas, and classical Hodgkin lymphoma. Here, we report of a 48-year-old male with hyper-IgE syndrome who developed a primary parotid gland diffuse large B cell lymphoma. Analysis for STAT3 mutations demonstrated that the causal mutation of hyper-IgE syndrome, R382Q, arose de novo in the patient and it was transmitted to three of his five children, all three of whom are clinically affected. We review the literature regarding lymphoma in hyper-IgE syndrome and the possible etiologic relationship with STAT3 mutations.

Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation

“…36 Along with recurrent bacterial infections, HIES patients also have difficulty controlling herpesviridae infections, 4 and may have an increased risk of lymphomas. 37 Given the role of NK cells in the immunosurveillance of virally-infected and malignant cells through recognition of NKG2D ligands, further investigation of NK-cell dysfunction in HIES patients is warranted.…”

A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency

“…The scarcity of intratumor infiltrative granzyme-B-positive T cells in lymphomas from IL-10R-deficient patients (relative to control DLBCLs) shown in immunohistochemical analyses and confirmed at transcriptomic level is consistent with the presence of a deficiency in an IL-10-triggered local antitumor immunity pathway. It is noteworthy that patients with heterozygous STAT3 mutations (resulting in partial loss of function) are also prone to the development of B-cell lymphomas 18,19 (albeit to a lesser extent). The observation that IL-10 signaling is STAT3 dependent supports the hypothesis in which the IL-10R/STAT3 pathway is involved in controlling lymphomas.…”

“…13 Infection with Epstein-Barr virus (EBV) and long-term administration of immunosuppressive medication are also associated with a slight increase in the risk of lymphoma in young children with colitis 14 and in adults with IBD. 15 A Mendelian predisposition to B-cell lymphoma 16 has been observed in some primary immunodeficiencies related to DNA repair (such as ataxia-telangiectasia 17 ) and dominant-negative STAT3 mutations 18,19 but not previously in the monogenic form of IBD. Here, we report on the occurrence and recurrence of diffuse large B-cell lymphomas (DLBCLs) in 5 children with IL-10R1 (n 5 1) or IL-10R2 deficiencies (n 5 4).…”

STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia

“…Of note, dominant negative mutations in the DNA-binding domain of STAT3 can cause Job syndrome, a primary immunodeficiency with predisposition to B-cell lymphomas; thus, systemic suppression of STAT3 function may have adverse consequences. [28][29][30][31] Further studies will determine whether there are distinct STAT3 signaling patterns among mutated and nonmutated samples that can measure the response to different Stat3 inhibitors.…”