Lineage Lymphomas Research Articles

Prevalence, clinical features, and survival outcome trends of 627 patients with primary cutaneous lymphoma over 29 years: a retrospective review from single tertiary center in Korea

The relative frequency of primary cutaneous lymphoma (PCL) subtypes shows wide variation across different geographical regions. This retrospective study was conducted in a tertiary referral center located in Korea to describe the relative frequency, demographics, survival outcomes, and temporal trend in PCL. A total of 627 PCL cases diagnosed between January 1994 and December 2022 were included. The majority of PCL cases (87.2%) were of T-/NK-cell lineage (CTCL), while the remaining cases (12.8%) were B-cell lineage lymphomas (CBCL). The prevalence of mycosis fungoides (MF) in CTCL increased significantly over time, while other CTCL subtypes, including primary cutaneous extranodal NK/T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma (SPTCL), decreased in frequency. Notably, the prevalence of CD4-positive small/medium T-cell lymphoproliferative disorder showed a substantial increase over time. Primary cutaneous marginal zone lymphoma was consistently the commonest CBCL subtype. Survival analysis demonstrated that CTCL had a more favorable 5-year overall survival (OS) than CBCL. OS rate of MF, SPTCL, and primary cutaneous peripheral T-cell lymphoma, NOS improved significantly over time. This study provides comprehensive insights into the dynamic change in the relative frequency and overall survival of PCL subtypes over time.

FCRL1 immunoregulation in B cell development and malignancy.

Immunotherapeutic targeting of surface regulatory proteins and pharmacologic inhibition of critical signaling pathways has dramatically shifted our approach to the care of individuals with B cell malignancies. This evolution in therapy reflects the central role of the B cell receptor (BCR) signaling complex and its co-receptors in the pathogenesis of B lineage leukemias and lymphomas. Members of the Fc receptor-like gene family (FCRL1-6) encode cell surface receptors with complex tyrosine-based regulation that are preferentially expressed by B cells. Among them, FCRL1 expression peaks on naïve and memory B cells and is unique in terms of its intracellular co-activation potential. Recent studies in human and mouse models indicate that FCRL1 contributes to the formation of the BCR signalosome, modulates B cell signaling, and promotes humoral responses. Progress in understanding its regulatory properties, along with evidence for its over-expression by mature B cell leukemias and lymphomas, collectively imply important yet unmet opportunities for FCRL1 in B cell development and transformation. Here we review recent advances in FCRL1 biology and highlight its emerging significance as a promising biomarker and therapeutic target in B cell lymphoproliferative disorders.

Targeting FoxO proteins induces lytic reactivation of KSHV for treating herpesviral primary effusion lymphoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus consisting of both latent and lytic life cycles. Primary effusion lymphoma (PEL) is an aggressive B-cell lineage lymphoma, dominantly latently infected by KSHV. The latent infection of KSHV is persistent and poses an obstacle to killing tumor cells. Like the "shock and kill" strategy designed to eliminate latent HIV reservoir, methods that induce viral lytic reactivation in tumor latently infected by viruses represent a unique antineoplastic strategy, as it could potentially increase the specificity of cytotoxicity in cancer. Inspired by this conception, we proposed that the induction of KSHV lytic reactivation from latency could be a potential therapeutic stratagem for KSHV-associated cancers. Oxidative stress, the clinical hallmark of PEL, is one of the most prominent inducers for KSHV reactivation. Paradoxically, we found that hydrogen peroxide (H2O2) triggers robust cytotoxic effects on KSHV-negative rather than KSHV-positive B lymphoma cells in a dose-dependent manner. Mechanistically, we identified forkhead box protein O1 (FoxO1) and FoxO3 as irrevocable antioxidant defense genes and both of them are upregulated by KSHV latent infection, which is essential for the promoted ROS scavenging in KSHV-positive B lymphoma cells. Pharmacological inhibition or functional knockdown of either FoxO1 or FoxO3 is sufficient to ablate the antioxidant ability and therefore increases the intracellular ROS level that further reverses KSHV from latency to active lytic replication in PEL cells, resulting in tremendous cell death both in vitro and in vivo. Additionally, the elevated level of ROS by inhibiting FoxO proteins further sensitizes PEL cells to ROS-induced apoptosis. Our study therefore demonstrated that the lytic reactivation of KSHV by inhibiting FoxO proteins is a promising therapeutic approach for PEL, which could be further extended to other virus-associated diseases.

High-Resolution Single Cell T-Cell Phenotyping of B-Cell Lineage Lymphomas Reveals Unique Immune Signatures and Potential Targetable Vulnerabilities

High-Resolution Single Cell T-Cell Phenotyping of B-Cell Lineage Lymphomas Reveals Unique Immune Signatures and Potential Targetable Vulnerabilities

Spectrum of Lymphoma: A Five Years’ Experience of Tertiary Care Centre in Eastern Nepal

Background: Immunophenotyping and improvement in classification system of lymphoma gains better epidemiological comparison in incidence and pattern. We aimed to study the spectrum and clinic-epidemiological profile of lymphoma and categorize the type and subtype of lymphoma according to 2008 WHO classification system. Methods: This hospital-based retrospective, cross-sectional study included all cases of lymphoma diagnosed in a 5-year period from January 2012 to December 2016. Demographic indices and the clinical details provided by various departments were noted in a proforma and the type and subtype of lymphoma were categorized according to 2008 WHO classification system. Results: There were a total of 47 cases of lymphoma, of which only 68% could be categorized. B cell lineage lymphomas comprised of 61.7% cases and the rest (6.3%) belonged to T cell lineage. Out of these, diffuse large B cell lymphoma (DLBCL) (21.2.% of total lymphoma) was found to be the commonest type of Non-Hodgkin’s lymphoma (NHL) followed by classical type of Hodgkin’s lymphoma (HL) (12.7% of total lymphoma). The highest number of cases were seen in the 6th decade. The mean age was 48.22 years for NHL and 42.60 years for HL. Male (70.2%) outnumbered female. Conclusion: Categorization of lymphoma according to the 2008 WHO classification system was achievable in 68% of cases with the aid of various immunophenotyping panels. B cell lineage lymphoma comprised of the majority of cases and DLBCL was seen to be the commonest type of lymphoma. Ancillary technique plays an important role in designating the spectrum of lymphoma.

Ablation of Cbl-b and c-Cbl in dendritic cells causes spontaneous liver cirrhosis via altering multiple properties of CD103+ cDC1s

The Casitas B-lineage lymphoma (Cbl) family proteins are E3 ubiquitin ligases implicated in the regulation of various immune cells. However, their function in dendritic cells (DCs) remains unclear. To investigate the role of Cbl family members in DCs, we created dendritic cell double-deficient Casitas B lymphoma-b (Cbl-b) and Casitas B lineage lymphoma (c-Cbl) mice by crossing Cbl-b−/− mice with c-Cblflox/flox CD11c-Cre+ mice. We found that specific deletion of Cbl-b and c-Cbl in CD11c+ cells, predominantly in DCs, led to liver fibrosis, cirrhosis, and accumulation of systemic conventional Type I DCs (cDC1s) due to enhanced cell proliferation and decreased cell apoptosis. In addition to a change in DC number, double knockout (dKO) cDC1s exhibited a partially activated status as indicated by high basal expression levels of certain cytokines and possessed an enhanced capacity to prime T cells. After adoptive transfer, dKO cDC1s could drive liver fibrosis too. In further experiments, we demonstrated that Cbl-b and c-Cbl could target signal transducer and activator of transcription 5 (STAT5), a transcriptional repressor for the pro-apoptotic protein Bim, to promote ubiquitination-mediated degradation and cell apoptosis in cDC1s. Further extensive experiments revealed that Cbl-b mediated K27-linked ubiquitination of lysine 164 of STAT5a while c-Cbl induced K29-linked ubiquitination of lysine 696 of STAT5a and K27-linked ubiquitination of lysine 140 and 694 of STAT5b. Thus, our findings indicate a functional redundancy of Cbl-b and c-Cbl in cDC homeostasis and maturation.

High Frequency of ASXL1 and IDH Mutations in Young Acute Myeloid Leukemia Egyptian Patients.

Background:Prognostication of AML patients depends on association of genetic and epigenetic abnormalities. We aimed to evaluate the frequency and prognostic significance of Additional Sex comb’s Like1 (ASXL1), Isocitrate Dehydrogenase (IDH) and Casitas B- lineage Lymphoma (CBL) mutations in AML assessing their association with different cytogenetic risk category. Methods:We used High Resolution Melting (HRM) technology that detects small differences in PCR amplified sequences by direct melting using EvaGreen saturating dye to analyze epigenetic mutations in 70 denovo AML patients. Results:Median age of AML patients was 39.5 years (18-75). ASXL1, IDH and CBL mutations were detected in 14 (20%), 10 (14%) and 5 (7%) patients, respectively. Mean age of ASXL1 and IDH mutants vs. wild type was 35.9±14.6 years and 42.9±14.4 years (p=0.114) and 46.7±15.2 years vs. 40.6±14.5 years (p=0.290), respectively. AML cytogenetic risk groups included low (25/70, 36%), intermediate (33/70, 47%) and high-risk (12/70, 17%). Nine/14 (64%) ASXL1 and 8/10 (80%) IDH mutants were classified as intermediate risk and 9 ASXL1 positive (64%) were adolescent and young adults (AYA). Overall survival (OS) of mutant ASXL1 vs. wild type was 1.1 years (95% CI 0.83-1.4) vs. 1.9 years (95% CI 0.71-7.51), respectively (p=0.056). OS of mutant IDH vs. wild type was 1.25 years (95% CI 0.85-1.6) vs. 1.8 years (95% CI 1.2-6.7), respectively (p=0.020). In intermediate risk cytogenetic group, ASXL1 and IDH mutants had shorter OS than wild type; 1.1 years (95% CI 0.97-1.2) vs. 2.1 years (95% CI 0.14-10.8) (p=0.002) and 1.8 years (95% CI 0.69-3.15) vs. 2.3 years (95% CI 1.1-5.5) (p=0.05), respectively. Conclusion: ASXL1 and IDH mutations occur at a high incidence among young Egyptian AML patients with intermediate risk cytogenetics and confer a poorer outcome. Integration of mutations into risk profiling may predict outcome and impact therapeutic approach of young AML patient with uncertain prognosis.

Clinical impact of cell-free serum Epstein-Barr virus status in patients with newly diagnosed malignant lymphoma.

BackgroundWe analyzed cell-free serum Epstein‒Barr virus (EBV) DNA to identify its prognostic role in patients with newly diagnosed lymphoma.MethodsWe retrospectively reviewed patients diagnosed with lymphoma between January 2014 and July 2020. Patients were enrolled according to the following criteria i) pathologically confirmed lymphomas according to the World Health Organization criteria, ii) age over 18 years, iii) serum EBV DNA measurement using polymerase chain reaction prior to first-line therapy, and iv) receipt of curative standard chemotherapy. In total, 263 patients met these criteria and were included in this study.ResultsSerum EBV DNA was detected in 79 patients (30.0%). Patients with positive serum EBV tended to be older (P=0.090), and the proportion of T-cell lineage lymphomas was higher than that of B-cell lymphomas (P=0.003). EBV positivity was significantly associated with more advanced disease based on the Ann Arbor staging system (P=0.008) and the International Prognostic Index (P=0.009). EBV positivity was also associated with higher disease relapse (P=0.038) and death rates (P=0.005). EBV-positive lymphomas further showed inferior long-term survival outcomes in terms of progression-free survival (PFS) (P=0.053) and overall survival (OS) (P=0.014). In the subgroup analyses, serum EBV positivity was a significant prognostic factor for patients with B-cell lineage lymphomas in terms of PFS (P=0.003) and OS (P=0.033).ConclusionWe demonstrated that cell-free serum EBV DNA status at the time of diagnosis has potential as a prognostic biomarker for patients with newly diagnosed malignant lymphomas.

Incidence Patterns of Patients with Two or More Lymphoid Malignancies in a Patient with a Prior History of Lymphoid Malignancy: A Population-Based Cancer Registry Study in Nagasaki, Japan

Background: The occurrence of second or more lymphoid malignancies in a patient with a prior history of lymphoid malignancy or a combination of two different subtypes of lymphoid malignancies at the same time in a patient have been sporadically reported. However, the incidence pattern of such cases in a large number setting has been rarely reported. Therefore, we investigated patients with two or more lymphoid malignancies in a population-based cancer registry.Methods: After approval of the institutional review board, we obtained a dataset of cases with lymphoid malignancies during the periods of 1985-2012 from the Nagasaki Prefectural Cancer Registry (NPCR), which was established in 1974, covers a population of approximately 1.56 million people in Nagasaki, Japan, and is known to be one of the highest data quality of the registry (the death certification only 9% and the proportion of morphological verification 79%). The overall age-adjusted incidence rate of lymphoid malignancies during 1985-2012 was already reported to be 20.5 for men and 12.9 for women (per 100,000 population). In the dataset, the lymphoid malignancies were coded according to the ICD-O-1, -2 and -3 systems. In case those were coded according to the ICD-O-1 and -2 systems, we substituted the corresponding ICD-O-3 code. For cases with undetermined codes, we reviewed the cancer registry sheets or pathological reports as much as possible. Finally, we confirmed all the lymphoid malignancies by ICD-O-3 histology codes 9650-9667, 9670-9699, 9700-9719, 9724-9729, 9731-9734, and 9760-9769. We then extracted cases having two or more histopathologically distinct lymphoid malignancies. We eliminated cases that were apparently considered to be recurrence cases of the first lymphoma. We analyzed the age- and sex-specific frequencies of multiple lymphomas among whole lymphoid malignancies, and characterized the combination pattern.Results: A total of 11,124 cases (male 5,981 cases and female 5,143 cases) of lymphoid malignancies were registered in the NPCR during 1985-2012. Among those, we identified 45 cases (male 27 and female 18) who had two or more different subtypes of lymphoid malignancies at same diagnosed date or at different diagnosed date. The median age at diagnosis of the first lymphoma of the 45 cases was 65.2 years (ranges from 26.6 years to 91.5 years). The overall prevalence of patients having multiple lymphoma among all patients with lymphoid malignancies during the periods of 1985-2012 was 0.40% (95%CI, 0.30-0.54%) for all, 0.45% (95%CI, 0.31-0.65%) for male, and 0.35% (95%CI, 0.21-0.55%) for female. There was no statistically significant difference in the prevalence by sex (Odds ratio, 1.29, P=0.40). Among the 45 cases, a patient was diagnosed as having two subtypes at same date, follicular lymphoma on spleen and Waldenstrom's macroglobulinemia. Another patient had three subtypes of lymphomas at different year; MALT on spleen in 2006, DLBCL on nasal in 2009, and Multiple Myeloma on bone marrow. The rest of the 43 patients developed two subtypes of lymphomas at different date. Median duration between date of the first lymphoid malignancy and date of the second one was 4.0 years (ranges from 0.1 years to 22 years). Among 45 cases, 23 (51.1%) had different cell lineage lymphomas between first and second lymphoma. The frequencies of the major combination pattern of first/second subtypes were as follows; MALT/DLBCL (n=4), MALT/mature T-lymphoma (n=4), DLBCL/ATL (n=3), DLBCL/ mature T-lymphoma (n=3), AILD/mature B-cell lymphoma (n=2), and others. From four patients with first Hodgkin's lymphoma, DLBCL (n=2), MALT (n=1), and ATL (n=1) developed as the second lymphoid malignancies.Conclusion: In the era of improved survival of patients with lymphoid malignancies, hematologists should be aware of the potential development of secondary or more lymphoid malignancies after treatment for first lymphoid malignancies. DisclosuresNo relevant conflicts of interest to declare.

Reflections about the Detection of Flower Cells in B-Cells Lymphomas

Flower or floral cells are multilobulated/petal-like nuclei, medium to large size cells usually present in cases of adult T-cell leukemia (ATL). However, since 2008, four cases of these cells, previously "restricted" to adult T leukemia, have been reported in B-cells lymphomas, many of them highly aggressive. Thus, this brief article aims to show how should be the assessment of these atypical cells in B lineage lymphomas and instigate more robust studies on the subject.

TAM receptors attenuate murine NK-cell responses via E3 ubiquitin ligase Cbl-b.

TAM receptors (Tyro3, Axl, and Mer) are receptor tyrosine kinases (RTKs) that are expressed by multiple immune cells including NK cells. Although RTKs typically enhance cellular functions, TAM receptor ligation blocks NK-cell activation. The mechanisms by which RTKs block NK-cell signaling downstream of activating receptors are unknown. In this report, we demonstrate that TAM receptors attenuate NK cell responses via the activity of E3 ubiquitin ligase Casitas B lineage lymphoma b (Cbl-b). Specifically, we show that Tyro3, Axl, and Mer phosphorylate Cbl-b, and Tyro3 ligation activates Cbl-b by phosphorylating tyrosine residues 133 and 363. Ligation of TAM receptors by their ligand Gas6 suppresses activating receptor-stimulated NK-cell functions such as IFN-γ production and degranulation, in a TAM receptor kinase- and Cbl-b-dependent manner. Moreover, Gas6 ligation induces the degradation of LAT1, a transmembrane adaptor protein required for NK cell activating receptor signaling, in WT but not in Cbl-b knock-out NK cells. Together, these results suggest that TAM receptors may attenuate NK-cell function by phosphorylating Cbl-b, which in turn dampens NK-cell activation signaling by promoting the degradation of LAT1. Our data therefore support a mechanism by which RTKs attenuate, rather than stimulate, signaling pathways via the activation of ubiquitin ligases.

C-Cbl: An Important Regulator and a Target in Angiogenesis and Tumorigenesis.

Casitas B lineage lymphoma (c-Cbl) is a multifunctional protein with a ubiquitin E3 ligase activity capable of degrading diverse sets of proteins. Although previous work had focused mainly on c-Cbl mutations in humans with hematological malignancies, recent emerging evidence suggests a critical role of c-Cbl in angiogenesis and human solid organ tumors. The combination of its unique structure, modular function, and ability to channelize cues from a rich network of signaling cascades, empowers c-Cbl to assume a central role in these disease models. This review consolidates the structural and functional insights based on recent studies that highlight c-Cbl as a target with tantalizing therapeutic potential in various models of angiogenesis and tumorigenesis.

EPR19-070: Incidence Pattern of Malignant Lymphoma by Cell-Lineage/Cell-Maturity Status in Nagasaki, Japan, 1985–2012: Preliminary Results

Background: Malignant lymphoma (ML) is a heterogeneous neoplasm with a wide range of etiological factors, pathological patterns, incidence rates, and outcomes. Most epidemiological studies have reported the incidence pattern of ML by simply dividing into 2 groups, Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL). However, differences in the incidence pattern by cell-lineage or by cell-maturity have been rarely evaluated. The aim of this study was to characterize the incidence pattern of ML by cell-lineage and cell-maturity in Japanese population. Methods: This is a descriptive study based on regional cancer registry data. We obtained a dataset of anonymized 12,645 cases with ICD-O histology codes of ML diagnosed 1960–2012 from the Nagasaki Prefectural Cancer Registry. From those, we excluded 1,477 records because of codes other than ML, diagnosed before 1985, and possible relapse records of identical cases. Records based on ICD-O-1 or ICD-O-2 were substituted by the corresponding ICD-O-3 code. We also treated patients having multiple types of MLs at same diagnosis date as a single case of “composite/discordant lymphoma,” and patients having multiple types of MLs at different diagnosis date as a single case based on the first lymphoma. We finally confirmed 11,118 patients of ML that occurred in 1985–2012. The overall age-adjusted incidence rate (per 100,000 population) during 1985–2012 was already reported to be 20.5 for men and 12.9 for women. Then we divided them into the following cell-lineage/maturity groups: precursor B (B1), mature B (B2), other B (B3), precursor T (T1), mature T/NK (T2), undetermined cell-lineage NHL (U), HL (H), and other lymphomas (O). Results: The median age at diagnosis of all patients was 69.7 years (interquartile range, 59.4–78.0 years) and male sex were 5,980 (53.8%). The frequency of B-cell lineage, T/NK-cell lineage, and Hodgkin lymphoma were 5,196 (46.7%), 3,257 (29.3%), and 209 (1.9%), respectively, with a significant sex difference (P<.0001). For B-cell maturity, B2 was predominant (84.8%), followed by B3 (14.4%) with a significant sex difference (P<.0001). In T-cell, T2 was predominant (99.4%). Conclusion: This preliminary analysis suggests a significant sex difference in the cell-lineage and cell-maturity of ML. Additional analysis to elucidate whether there are any differences in the incidence pattern by cell-lineage and by cell-maturity of ML between general population and Nagasaki atomic bomb survivors are underway.

Analyses and treatment of simultaneous bi-lineage malignancies of myeloid leukemia and lymphoma: Two case reports and a literature review.

The present study reports two cases of concurrently diagnosed T-lymphoblastic lymphoma (T-LBL) and chronic myeloid leukemia (CML). The literature review revealed that myeloid leukemia may appear secondary to Hodgkin lymphoma or non-Hodgkin lymphoma. However, simultaneous bi-lineage hematologic malignancies are rarely seen and the prognosis is worse than single lineage lymphoma or myeloid leukemia. There were no standard therapies. All simultaneous bi-lineage malignancies of myeloid leukemia and lymphoma reported in Pubmed were combined with the present two cases, to analyses its pathogenesis, features and treatment. It was concluded that the prognosis of bi-lineage hematologic malignancies was poor, however allogeneic hematopoietic stem cell transplantation could improve survival (P=0.033).

MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress.

Hypomorphic mutations in the genes encoding the MRE11/RAD50/NBS1 (MRN) DNA repair complex lead to cancer-prone syndromes. MRN binds DNA double-strand breaks, where it functions in repair and triggers cell-cycle checkpoints via activation of the ataxia-telangiectasia mutated kinase. To gain understanding of MRN in cancer, we engineered mice with B lymphocytes lacking MRN, or harboring MRN in which MRE11 lacks nuclease activities. Both forms of MRN deficiency led to hallmarks of cancer, including oncogenic translocations involving c-Myc and the immunoglobulin locus. These preneoplastic B lymphocytes did not progress to detectable B lineage lymphoma, even in the absence of p53. Moreover, Mre11 deficiencies prevented tumorigenesis in a mouse model strongly predisposed to spontaneous B-cell lymphomas. Our findings indicate that MRN cannot be considered a standard tumor suppressor and instead imply that nuclease activities of MRE11 are required for oncogenesis. Inhibition of MRE11 nuclease activity increased DNA damage and selectively induced apoptosis in cells overexpressing oncogenes, suggesting MRE11 serves an important role in countering oncogene-induced replication stress. Thus, MRE11 may offer a target for cancer therapeutic development. More broadly, our work supports the idea that subtle enhancements of endogenous genome instability can exceed the tolerance of cancer cells and be exploited for therapeutic ends. Cancer Res; 77(19); 5327-38. ©2017 AACR.

Sortase A-Generated Highly Potent Anti-CD20-MMAE Conjugates for Efficient Elimination of B-Lineage Lymphomas.

Antibody-drug conjugate (ADC) targeting antigens expressed on the surface of tumor cells are an effective approach for delivering drugs into the cells via antigen-mediated endocytosis. One of the well-known tumor antigens, the CD20 of B-lymphocyte, has long been suggested to be noninternalizing epitope, and is thus not considered a desirable target for ADCs. Here, sortase A (srtA)-mediated transpeptidation is used to specifically conjugate triple glycine-modified monomethyl auristatin E (MMAE), a highly toxic antimitotic agent, to anti-CD20 ofatumumab (OFA) equipped with a short C-terminal LPETG (5 amino acids) tag at heavy chain (HL), which generates ADCs that show extremely strong potency in killing CD20 positive cancer cells. One of the srtA-generated ADCs with a cleavable dipeptide linker (valine-citrulline, vc), OFA-HL-vcMMAE, shows IC50 values ranging from 5 pg mL-1 to 4.1 ng mL-1 against CD20+ lymphoma cells. Confocal laser scanning microscopy confirms that OFA-HL-vcMMAE internalization by Ramos cells is significantly improved compared to OFA alone, consistent with the high antitumor activity of the new ADC. OFA-HL-vcMMAE, at 5 mg kg-1 dose, is able to eliminate tumors with mean volume ≈400 mm3 while no obvious drug-related toxicity is observed. The results show that srtA-generated OFA-MMAE conjugate system provides a viable strategy for targeting CD20+ B lineage lymphomas.

Rare Non-Hodgkin Lymphoma in Childhood; A Single Center Experience

Background: Among pediatric non-Hodgkin lymphomas, there are 4 major subtypes: Burkitt lymphoma, lymphoblastic lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma. Understanding of other rare subtypes derives only from small pediatric case series. We report our institutional experi ence with rare pediatric NHLs. Methods: Thirty-six cases of rare NHL subtypes diagnosed at the Asan Medical Center from 1995 to 2015 were evaluated. We retrospectively reviewed the clinical and pathologic features and outcomes of these patients, excluding peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), and extranodal NK/T-cell lymphoma (ENKL), on which we have previously reported. Results: There were 23 cases of T-cell lineage (13 PTCL, 6 ENKL, 2 subcutaneous panniculitis-like T-cell lymphoma, 1 primary cutaneous CD4 ＋ small/medium sized T-cell lymphoma, 1 enteropathy-associated T-cell lymphoma) and 13 cases of B-cell lineage lymphoma (5 marginal zone lymphoma, 6 primary mediastinal large B-cell lymphoma, 2 immunoblastic and plasmablastic lymphoma). All patients were treated with chemotherapy with or without surgery, except 4 out of 5 patients with marginal zone lymphoma who received surgery only. Two patients died and 6 patients relapsed. One patient with primary mediastinal large B-cell lymphoma received autologous peripheral blood stem cell transplantation. The 5-year overall survival and event-free survival rates of rare pediatric NHL excluding PTCL, NOS, and ENKL was 80.0% and 72.0%, respectively. Conclusion: Children diagnosed with rare pediatric NHL other than PTCL, NOS, and ENKL showed variable incidence and treatment outcomes. Multicenter studies in larger cohorts are needed for better understanding of these rare NHL subtypes in childhood.

E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor–mediated antifungal innate immunity

Activation of various C-type lectin receptors (CLRs) initiates potent proinflammatory responses against various microbial infections. However, how activated CLRs are negatively regulated remains unknown. In this study, we report that activation of CLRs Dectin-2 and Dectin-3 by fungi infections triggers them for ubiquitination and degradation in a Syk-dependent manner. Furthermore, we found that E3 ubiquitin ligase Casitas B-lineage lymphoma protein b (Cbl-b) mediates the ubiquitination of these activated CLRs through associating with each other via adapter protein FcR-γ and tyrosine kinase Syk, and then the ubiquitinated CLRs are sorted into lysosomes for degradation by an endosomal sorting complex required for transport (ESCRT) system. Therefore, the deficiency of either Cbl-b or ESCRT subunits significantly decreases the degradation of activated CLRs, thereby resulting in the higher expression of proinflammatory cytokines and inflammation. Consistently, Cbl-b-deficient mice are more resistant to fungi infections compared with wild-type controls. Together, our study indicates that Cbl-b negatively regulates CLR-mediated antifungal innate immunity, which provides molecular insight for designing antifungal therapeutic agents.

Integrin CD11b attenuates colitis by strengthening Src-Akt pathway to polarize anti-inflammatory IL-10 expression.

Interleukin-10 (IL-10) plays a central role in regulation of intestinal mucosal homeostasis and prevention of inflammatory bowel disease (IBD). We previously reported that CD11bhi regulatory dendritic cells (DCs) can produce more IL-10, and CD11b can negatively regulate Toll-like receptors (TLRs)-induced inflammatory responses in macrophages. However whether CD11b and its signaling can control autoimmunity via IL-10 production remains unclear. Here we found that CD11b deficient (Itgam−/−) mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis, with more tumor necrosis factor α (TNF-α) while less IL-10 production. CD11b inhibited nuclear factor-kappa B (NF-κB) while promoted activator protein 1 (AP-1) activation through activating sarcoma oncogene (Src), leading to decreased TNF-α while increased IL-10 production. Src interacted with and promoted c-casitas B lineage lymphoma proto-oncogene (c-Cbl)-mediated degradation of the inhibitory subunit p85 of phosphatidylinositol 3-kinase (PI3K). Importantly, Src inhibitor dasatinib aggravated DSS-induced colitis by decreasing IL-10 while increasing TNF-α in vivo. Therefore, CD11b promotes IL-10 production by activating Src-Akt signal pathway. An axis of CD11b-Src pathway is important in balancing homeostasis of TLR-induced pro-inflammatory and anti-inflammatory responses.

NADPH Oxidase 1 Activity and ROS Generation Are Regulated by Grb2/Cbl-Mediated Proteasomal Degradation of NoxO1 in Colon Cancer Cells.

The generation of reactive oxygen species (ROS) is required for proper cell signaling, but must be tightly regulated to minimize deleterious oxidizing effects. Activation of the NADPH oxidases (Nox) triggers ROS production and, thus, regulatory mechanisms exist to properly control Nox activity. In this study, we report a novel mechanism in which Nox1 activity is regulated through the proteasomal degradation of Nox organizer 1 (NoxO1). We found that through the interaction between NoxO1 and growth receptor-bound protein 2 (Grb2), the Casitas B-lineage lymphoma (Cbl) E3 ligase was recruited, leading to decreased NoxO1 stability and a subsequent reduction in ROS generation upon epidermal growth factor (EGF) stimulation. Additionally, we show that EGF-mediated phosphorylation of NoxO1 induced its release from Grb2 and facilitated its association with Nox activator 1 (NoxA1) to stimulate ROS production. Consistently, overexpression of Grb2 resulted in decreased Nox1 activity, whereas knockdown of Grb2 led to increased Nox1 activity in response to EGF. CRISPR/Cas9-mediated NoxO1 knockout in human colon cancer cells abrogated anchorage-independent growth on soft agar and tumor-forming ability in athymic nude mice. Moreover, the expression and stability of NoxO1 were significantly increased in human colon cancer tissues compared with normal colon. Taken together, these results support a model whereby Nox1 activity and ROS generation are regulated by Grb2/Cbl-mediated proteolysis of NoxO1 in response to EGF, providing new insight into the processes by which excessive ROS production may promote oncogenic signaling to drive colorectal tumorigenesis.