Multi-Centric Castleman's Disease

Researchers have discovered a key mechanism used by Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), to induce cancer. The research points to effective new treatment options for KSHV-associated cancers, including Kaposi's sarcoma, primary effusion lymphoma, and HHV8-associated multicentric Castleman disease. Cleveland Clinic researchers have discovered a key mechanism used by Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), to induce cancer. The research points to effective new treatment options for KSHV-associated cancers, including Kaposi's sarcoma, primary effusion lymphoma, and HHV8-associated multicentric Castleman disease. "Our findings have significant implications: viruses cause between 10% to 20% of cancers worldwide, a number that is constantly increasing as new discoveries are made. Treating virus-induced cancers with standard cancer therapies can help shrink tumors that are already there, but it doesn't fix the underlying problem of the virus," said Jun Zhao, Ph.D., of Cleveland Clinic Florida Research & Innovation Center. "Understanding how pathogens transform a healthy cell into a cancer cell uncovers exploitable vulnerabilities and allows us to make and repurpose existing drugs that can effectively treat virus-associated malignancies." The Nature Communicationsstudy, led by Dr. Zhao, reveals that KSHV manipulates two human enzymes called CDK6 and CAD to reshape the way human cells produce new nucleotides -- the building blocks of DNA and RNA -- and process glucose. The changes to how infected cells grow and how KSHV persists put cells at a much higher risk of forming tumors and play a crucial role in causing cancer. The team showed the virus activates a specific pathway driving cell metabolism and proliferation. Inhibiting this process with existing FDA-approved breast cancer drugs reduced KSHV replication, blocked lymphoma progression and shrunk existing tumors in preclinical models. Like other herpesviruses, KSHV often has no symptoms initially and remains in the body after primary infection. The virus stays dormant, suppressed by the immune system. However, KSHV can reactivate when immunity is weakened -- as in older people, those with HIV/AIDS, and transplant recipients. In these high-risk groups, the now active virus can trigger aggressive cancers. KSHV-induced cancers are fast-acting, aggressive and difficult to treat. An estimated 10% of people in North America and Northern Europe have KSHV, but this ranges throughout the globe. More than 50% of individuals in parts of Northen Africa are estimated to have the virus. Experts estimate these rates are higher, as KSHV often goes undiagnosed because of lack of symptoms. These findings have implications that reach past KSHV; researchers can apply knowledge about KSHV to other cancer-associated viruses that might use the same process to cause cancer. To understand the cells' metabolic processes to uncover the virus's vulnerabilities, Dr. Zhao collaborated with Michaela Gack, Ph.D., Scientific Director of the Florida Research & Innovation Center. Rapidly replicating cancer cells reprogram metabolism to fuel growth. Meanwhile, most viruses cannot produce energy or necessary molecules on their own, so they rely on human cells to do the work for them. The team found that the virus takes over the host protein CDK6 and CAD, causing the infected cells to produce extra metabolites, which allows faster replication of the virus and an uncontrolled proliferation of the cells. The research team treated pre-clinical models with a CDK6-blocking drug, Palbociclib, an FDA-approved breast cancer medication, as well as a compound targeting CAD. They saw significant decreases in tumor size and increases in cancer survival rates: most tumors virtually disappeared after about a month of treatment, and remaining tumors shrank around 80%. Survival increased to 100% for selected lymphoma cell lines. Dr. Zhao and his team are working to better understand the connections among KSHV, CDK6/CAD pathway, and cancer formation. With the knowledge they obtain, they plan to implement and refine their experimental drug combinations for clinical trials. "Cellular metabolism could be hijacked by both viruses and cancers for pathogenesis," said Dr. Zhao. "By investigating these metabolic rewiring mechanisms, we aim to find the Achilles' heel of cancer-causing viruses and non-viral cancers. I'm excited to see what the future of this work holds."

The viruses Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) have been linked to several cancers. For the first time, UNC School of Medicine scientists have discovered that these viruses use a human protein called barrier-to-autointegration factor 1, or BAF, to evade our innate immune response, allowing the viruses to spread and cause disease. These findings, published in Nature Communications, suggest that BAF and related proteins could be therapeutic targets to prevent these viruses from spreading and leading to cancers, such as Kaposi sarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, multicentric Castleman disease, nasopharyngeal carcinoma, and gastric cancer. "Viruses are in a constant battle with the cellular immune system, which includes the protein cyclic GMP-AMP synthase, or cGAS, which binds to viral DNA and sounds the alarm to trigger immune responses and fight the viral invaders," said senior author Blossom Damania, PhD, the Boshamer Distinguished Professor of Microbiology and Immunology and member of the Lineberger Comprehensive Cancer Center. "We've discovered that KSHV and EBV use a different host cell protein, BAF, to prevent cGAS from sounding the alarm." Viruses have evolved with humans for millions of years, so it's no surprise they've evolved tricks to evade our natural, or innate, immune responses. Finding out precisely how viruses do this is the basis for creating vaccines and therapeutics to overcome their tricks. In the case of KSHV and EBV, the expression of BAF is increased upon infection, suggesting that these viruses take advantage of this host protein to blunt the immune response to infection. In a series of experiments, Damanias lab found that BAF contributes to the degradation of the cGAS DNA sensor. With less cGAS protein available in the infected cell to detect DNA, the cells mount weaker immune responses, which allows these two viruses to replicate and spread more efficiently. "BAF enables EBV and KSHV to reactivate from latency, replicate, and make more of themselves," said first author Grant Broussard, a graduate student in the Genetics and Molecular Biology Curriculum at UNC Lineberger. "Our study highlights the prominent role that DNA detection pathways like the cGAS pathway play in controlling viral infection." He stressed that disrupting BAF activity with targeted therapies could reduce its immunosuppressive effects, thus restricting replication of these viruses to prevent the spread of disease. Damania, who is a Leukemia and Lymphoma Society Scholar and a Burroughs Wellcome Fund Investigator in Infectious Diseases, added, "Preventing lytic replication will prevent transmission of these viruses and also reduce the global cancer burden associated with these two viruses." Broussard, G., Ni, G., Zhang, Z. et al. Barrier-to-autointegration factor 1 promotes gammaherpesvirus reactivation from latency. Nat Commun 14, 434, 2023. doi: 10.1038/s41467-023-35898-2

A new study confirms that idiopathic plasmacytic lymphadenopathy is an independent disease subtype of idiopathic multicentric Castleman disease. Idiopathic plasmacytic lymphadenopathy (IPL) is a clinical condition marked by an excessive amount of antibody production due to the proliferation of polyclonal plasma cells in the lymph nodes. At present, it is not clear if IPL is a subtype of idiopathic multicentric Castleman disease (iMCD)-not otherwise specified (NOS). In a new study, researchers from Okayama University have found clinicopathological evidence needed to establish a separate disease unit for IPL under iMCD-NOS. Multicentric Castleman disease (MCD) comprises a heterogenous group of rare disorders that exhibit generalized symptoms such as swelling of lymph nodes, anemia, fever, and fatigue. The causative factors underlying MCD include Kaposi sarcoma-associated herpesvirus (KSHV)/ human herpesvirus 8 (HHV8) infections. KSHV/HHV8-negative MCD without association with the POEMS (polyneuropathy, organomegaly, endocrinopathy, M proteins, and skin changes) syndrome are termed "idiopathic," i.e., diseases with no identifiable cause, and are thus referred to as "iMCD." At present, specific clinical manifestations or diagnostic criteria have not been identified for iMCD, which often results in treatment delay. iMCD is further classified as iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). With additional research efforts, iMCD-NOS, which is highly heterogenous, could be classified into various subtypes. Interestingly, a disease known as idiopathic plasmacytic lymphadenopathy (IPL), which is characterized by hypergammaglobulinemia, i.e., high levels of serum immunoglobulins, and histologically mature plasma cell proliferation in the lymph nodes, is considered a part of iMCD-NOS due to their clinicopathological similarity. However, till date, no study has validated if IPL has distinct clinicopathologic features compared to other iMCD-NOS. This motivated a team of researchers led by Assistant Professor Asami Nishikori, including Associate Professor Midori Filiz Nishimura, and Professor Yasuharu Sato from Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences, Japan to conduct a thorough clinicopathological examination of IPL and others in iMCD. Their findings were published on September 7, 2022, in the International Journal of Molecular Sciences. "We wanted to determine whether IPL has distinct and uniform clinicopathologic features compared to other subtypes (non-IPL) in iMCD-NOS," remarks Assist. Prof. Nishikori while discussing the motivation behind the study. The team analyzed lymph node specimens derived from 42 Japanese patients with lymph node involvement of iMCD-NOS, who met the consensus diagnostic criteria of iMCD and were negative for KSHV/HHV8 infections. Upon further examination, the team classified 34 of the 42 patients as the IPL group and the remaining 8 as the non-IPL group. On grading histological features such as vascularity, plasmacytosis (high proportion of plasma cells), atrophic and hyperplastic germinal centers (GCs), the team identified significant pathological differences between the specimens of the IPL and non-IPL groups. The IPL group demonstrated greater plasmacytosis and hyperplastic GCs compared to the non-IPL group. Conversely, the vascularity of the non-IPL group was higher than that of the IPL group. Clinically, the IPL group exhibited higher platelet count and serum antibody (immunoglobulin G) levels, with lesser fluid retention in pleural and/or abdominal cavity. The frequency of disease-specific autoantibody detection was also different between the groups. In addition, the clinical course and treatment responses in the two groups were also distinct. Upon treatment with tocilizumab, an anti-interleukin 6 receptor monoclonal antibody approved to treat iMCD in Japan, there was a significant improvement in the condition of patients with IPL. In contrast, patients with non-IPL responded poorly to the drug and showed progressed disease activity, requiring more intensive treatment. These findings were consistent with those of previous studies that suggest that the clinical course of IPL disease progression is slower as compared to the non-IPL group, and with a superior response to anti-IL-6 agents. Discussing these findings, Assist. Prof. Nishikori states "Given the heterogeneity of non-IPL cases, we must try to identify its primary cause. Molecular analysis could lead to a better understanding of disease pathology and the development of subsequent targeted therapies." To sum up, these findings have established IPL as a clinicopathologically uniform disease, which can be reclassified into an independent subtype of iMCD. So, what are the future implications of these findings? "It is critical that patients get the most out of any treatment modules. Studies on iMCD subtype-specific diagnostic biomarkers, treatment, and follow-up are thus warranted in the future to improve the clinical outcomes for these patients," concludes Assist. Prof. Nishikori.