Review of the biologic and clinical significance of genetic mutations in angioimmunoblastic T‐cell lymphoma

Fukumoto, Kota; Nguyen, Tran B.; Sakata‐Yanagimoto, Mamiko

doi:10.1111/cas.13393

Cited by 36 publications

(34 citation statements)

References 60 publications

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“…Mutations in AIFM-1 are related to fatal encephalomyopathy in infants ( 149 ). Recurrent mutations in IDH2 are associated with angioimmunoblastic T cell lymphoma ( 150 ). Polymorphisms in MnSOD can lead to abortion during the first trimester of pregnancy ( 151 ).…”

Section: Discussionmentioning

confidence: 99%

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

et al. 2018

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Lack of immune system cells or impairment in differentiation of immune cells is the basis for many chronic diseases. Metabolic changes could be the root cause for this immune cell impairment. These changes could be a result of altered transcription, cytokine production from surrounding cells, and changes in metabolic pathways. Immunity and mitochondria are interlinked with each other. An important feature of mitochondria is it can regulate activation, differentiation, and survival of immune cells. In addition, it can also release signals such as mitochondrial DNA (mtDNA) and mitochondrial ROS (mtROS) to regulate transcription of immune cells. From current literature, we found that mitochondria can regulate immunity in different ways. First, alterations in metabolic pathways (TCA cycle, oxidative phosphorylation, and FAO) and mitochondria induced transcriptional changes can lead to entirely different outcomes in immune cells. For example, M1 macrophages exhibit a broken TCA cycle and have a pro-inflammatory role. By contrast, M2 macrophages undergo β-oxidation to produce anti-inflammatory responses. In addition, amino acid metabolism, especially arginine, glutamine, serine, glycine, and tryptophan, is critical for T cell differentiation and macrophage polarization. Second, mitochondria can activate the inflammatory response. For instance, mitochondrial antiviral signaling and NLRP3 can be activated by mitochondria. Third, mitochondrial mass and mobility can be influenced by fission and fusion. Fission and fusion can influence immune functions. Finally, mitochondria are placed near the endoplasmic reticulum (ER) in immune cells. Therefore, mitochondria and ER junction signaling can also influence immune cell metabolism. Mitochondrial machinery such as metabolic pathways, amino acid metabolism, antioxidant systems, mitochondrial dynamics, mtDNA, mitophagy, and mtROS are crucial for immune functions. Here, we have demonstrated how mitochondria coordinate to alter immune responses and how changes in mitochondrial machinery contribute to alterations in immune responses. A better understanding of the molecular components of mitochondria is necessary. This can help in the development of safe and effective immune therapy or prevention of chronic diseases. In this review, we have presented an updated prospective of the mitochondrial machinery that drives various immune responses.

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Section: Discussionmentioning

confidence: 99%

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

et al. 2018

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“…DNMT3A is an enzyme that catalyzes the transfer of a methyl group on cytosine residues in the CpG dinucleotide leading to repression of target gene expression. In AITL patients, inactivating mutations in DNMT3A were identified in 20-30% of the cases 69,70 . A hotspot mutation (p.R882H) in DNMT3A accounts for 15% of the DNMT3A mutations in AITL.…”

Section: Dmt3a Mutations In Aitlmentioning

confidence: 99%

New preclinical models for angioimmunoblastic T-cell lymphoma: filling the GAP

et al. 2020

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Mouse models are essential to study and comprehend normal and malignant hematopoiesis. The ideal preclinical model should mimic closely the human malignancy. This means that these mice should recapitulate the clinical behavior of the human diseases such as cancer and therapeutic responses with high reproducibility. In addition, the genetic mutational status, the cell phenotype, the microenvironment of the tumor and the time until tumor development occurs, should be mimicked in a preclinical model. This has been particularly challenging for human angioimmunoblastic lymphoma (AITL), one of the most prominent forms of peripheral T-cell lymphomas. A complex network of interactions between AITL tumor cells and the various cells of the tumor microenvironment has impeded the study of AITL pathogenesis in vitro. Very recently, new mouse models that recapitulate faithfully the major features of human AITL disease have been developed. Here, we provide a summary of the pathology, the transcriptional profile and genetic and immune-phenotypic features of human AITL. In addition, we give an overview of preclinical models that recapitulate more or less faithfully human AITL characteristics and pathology. These recently engineered mouse models were essential in the evaluation of novel therapeutic agents for possible treatment of AITL, a malignancy in urgent need of new treatment options. Angioimmunoblastic T-cell lymphoma: a challenging complex malignancy Clinical aspects Angioimmunoblastic T-cell lymphoma (AITL) belongs since 2016 after revision of the world health organization (WHO) classification to the nodal T-cell lymphomas with follicular helper T-cell (Tfh) phenotype 1. AITL is a rare, aggressive lymphoma with little treatment options. Overall survival is generally poor with a five-year median survival rate of 32% 2,3. It represents only 1-2% of the non-Hodgkin's lymphomas. However, AITL appears to be the most prevalent PTCL, representing up to 35% of the noncutaneous peripheral T-cell lymphomas 2,4-6. AITL pathology develops late in life with a median age at onset of 59-65 years and patients display a generalized lymphoadenopathy 7,8. Seventy percent of the patients have bone marrow involvement and unfortunately early stage detection of AITL is very uncommon (10%) 9. Disease symptoms resemble closely an infection inducing immunologic hyper-activation (fever, rash, loss of weight, hemolytic anemia 2,5) (Fig. 1). AITL has particular clinical and pathological features, associated with splenomegaly, hepatomegaly and enlarged lymph nodes showing effacement of normal architecture and appearance of endothelial venules 3 (Fig. 1). Other typical clinical manifestation of AITL are cutaneous lesions also called skin rash in 20-50% of the patients and accumulation of abdominal ascites 5,10-13. These patients often test positive for autoimmunity including detection of rheumatoid factor, anti-smooth muscle, and nuclear autoantibodies 14. They also present a general increase in immunoglobulins called hypergammaglobulemia (30%) 7,12 .

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“…AITL is more common in elderly patients attributed to the age-related premalignant mutations. 12 To date, the largest study recruited 1207 AITL patients confirmed that age > 60 years, progressive stage, and male were adverse factors of prognosis. 13 Somatic mutations were detected in 95% of individuals aged between 50 and 60 years old.…”

Section: Discussionmentioning

confidence: 98%

Development of a Novel Clinical Prognostic Model for Patients With Angioimmunoblastic T-Cell Lymphoma

Huang

Zhang

Gao

et al. 2020

Technol Cancer Res Treat

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In this study we aimed to identify a set of prognostic factors for angioimmunoblastic T-cell lymphoma (AITL) and establish a novel prognostic model. The clinical data of 64 AITL patients enrolled to the Fourth Hospital of Hebei Medical University (from 2012 Jan to 2017 May) were retrospectively analyzed. The estimated 5-year overall survival and progression-free survival of this cohort of patients were 45.8% and 30.8%, respectively. Univariate analysis showed that age > 60 years, performance status ≥2, Ann Arbor stage III/IV, lactate dehydrogenase > 250 U/L, serum albumin (ALB) < 30 g/l, Coombs test positive, and Ki-67 rate ≥ 70% were significantly associated with poor prognosis. Multivariate analysis demonstrated that age > 60 years, ALB < 30 g/l, Ki-67 rate ≥ 70%, and Coombs test positive were independent prognosis factors for AITL. Here a new prognostic model, named as AITLI, was constructed using the top 5 significant prognostic factors for AITL prognostic prediction. The AITL patients were stratified into 3 risk groups: low, intermediate, and high risk groups. The new prognostic model AITLI showed better performance in predicting prognosis than the International Prognostic Index (IPI) and the prognostic index for PTCL, not otherwise specified (PIT) that were wisely used to predict the outcome for patients with other subtypes of lymphoma.

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Review of the biologic and clinical significance of genetic mutations in angioimmunoblastic T‐cell lymphoma

Cited by 36 publications

References 60 publications

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

New preclinical models for angioimmunoblastic T-cell lymphoma: filling the GAP

Development of a Novel Clinical Prognostic Model for Patients With Angioimmunoblastic T-Cell Lymphoma

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