A Rare Case of Non-IgM Lymphoplasmacytic Lymphoma with Unusual Lack of Immunoglobulin Light Chain Production.

BACKGROUND Non-IgM lymphoplasmacytic lymphoma (LPL) is a rare subtype of LPL, constituting less than 5% of the cases, and is often associated with IgG, IgA, or light chain paraproteins and is rarely a non-secretor. Non-IgM LPL remains poorly studied, and the differential diagnosis from other small B-cell lymphomas with plasmacytic differentiation and plasma cell neoplasm is challenging. CASE REPORT A 67-year-old woman presented with weight loss, persistent anemia, and borderline leukopenia. Serum protein electrophoresis and immunofixation demonstrated a faint IgG and kappa band against a dense polyclonal background. Bone marrow biopsy revealed hypercellular marrow with involvement by abnormal B cells with undetectable surface and cytoplasmic immunoglobulin light chains. Interestingly, these B cells showed no expression of light chains or production of IgG and IgM; however, they showed production of intracytoplasmic IgA. The concomitant neoplastic plasma cells also displayed no definitive light chain expression. Both IgH and IgK gene rearrangements were positive for clonal process. Molecular studies showed positive MYD88 L265P mutation and CXCR4 mutation (c.1013C>G). The overall findings confirmed marrow involvement by non-IgM LPL. The patient received 6 cycles of rituximab and bendamustine treatment, and no residual marrow involvement was found on the follow-up bone marrow biopsy. CONCLUSIONS We report a non-IgM LPL case featuring no light chain production and no heavy chain secretion, which we believe is the first reported case of this kind in the literature.

Radiologic and clinicopathologic features of eosinophilic solid and cystic renal cell carcinoma: report of two cases and review of literature.

Eosinophilic Solid and Cystic Renal Cell Carcinoma (ESC RCC) is a rare entity described in the latest WHO Classification of Urinary and Male Genital Tumours (2022 edition). It is a neoplasm that occurs most often in a sporadic setting, with no association with tuberous sclerosis complex (TSC). It typically presents as a well demarcated, non-encapsulated lesion, with solid and cystic architecture, composed of cells with voluminous eosinophilic cytoplasm and cytoplasmic stippling. Tumor cells are at least focally immunohistochemically (IHC) reactive for CK20. CD10 and Cathepsin K are positive in most cases. Consistent somatic mutually exclusive mutations in the TSC1 and TSC2 genes are detected in ESC RCC. We describe two ESC RCC cases diagnosed at our institution. Both cases occurred in female patients, ages of 33 and 64, respectively. Both patients had no evidence of TSC and both lesions were found incidentally, by imaging studies, at an early stage. Macroscopic and microscopic findings in both neoplasms were classic. One case was analyzed by molecular testing and TSC2 gene mutation was detected. Both cases had focal positivity of CD10 and Cathepsin K by IHC. Both tumors were stage pT1a at diagnosis and the patients remained free of disease after resection. It has been proposed that TSC1/2 can be a molecular marker for ESC RCC and be used to expand the morphologic spectrum of ESC RCC. As a novel rare subtype of renal cell carcinoma, with very limited data on molecular evaluation, it is useful to document these newly diagnosed ESC RCC cases.

Essential role of the linear ubiquitin chain assembly complex and TAK1 kinase in A20 mutant Hodgkin lymphoma.

More than 70% of Epstein-Barr virus (EBV)-negative Hodgkin lymphoma (HL) cases display inactivation of TNFAIP3 (A20), a ubiquitin-editing protein that regulates nonproteolytic protein ubiquitination, indicating the significance of protein ubiquitination in HL pathogenesis. However, the precise mechanistic roles of A20 and the ubiquitination system remain largely unknown in this disease. Here, we performed high-throughput CRISPR screening using a ubiquitin regulator-focused single-guide RNA library in HL lines carrying either wild-type or mutant A20. Our CRISPR screening highlights the essential oncogenic role of the linear ubiquitin chain assembly complex (LUBAC) in HL lines, which overlaps with A20 inactivation status. Mechanistically, LUBAC promotes IKK/NF-κB activity and NEMO linear ubiquitination in A20 mutant HL cells, which is required for prosurvival genes and immunosuppressive molecule expression. As a tumor suppressor, A20 directly inhibits IKK activation and HL cell survival via its C-terminal linear-ubiquitin binding ZF7. Clinically, LUBAC activity is consistently elevated in most primary HL cases, and this is correlated with high NF-κB activity and low A20 expression. To further understand the complete mechanism of NF-κB activation in A20 mutant HL, we performed a specifically designed CD83-based NF-κB CRISPR screen which led us to identify TAK1 kinase as a major mediator for NF-κB activation in cells dependent on LUBAC, where the LUBAC-A20 axis regulates TAK1 and IKK complex formation. Finally, TAK1 inhibitor Takinib shows promising activity against HL in vitro and in a xenograft mouse model. Altogether, these findings provide strong support that targeting LUBAC or TAK1 could be attractive therapeutic strategies in A20 mutant HL.

A20 and RBX1 Regulate Brentuximab Vedotin Sensitivity in Hodgkin Lymphoma Models.

PURPOSE: For patients with refractory/relapsed Hodgkin lymphoma (roughly 20% of total cases), few effective therapeutic options exist. Currently, brentuximab vedotin (BV), a drug-conjugated anti-CD30 antibody, is one of the most effective approved therapy agents for these patients. However, many patients do not achieve complete remission and ultimately develop BV-resistant disease, necessitating a more detailed understanding of the molecular circuitry that drives BV sensitivity and the mechanism of BV resistance. EXPERIMENTAL DESIGN: Here, we established a ubiquitin regulator-focused CRISPR library screening platform in Hodgkin lymphoma and carried out a drug sensitization screen against BV to identify genes regulating BV treatment sensitivity. RESULTS: Our CRISPR library screens revealed the ubiquitin-editing enzymes A20 and RBX1 as key molecule effectors that regulate BV sensitivity in Hodgkin lymphoma line L428. A20 negatively regulates NF-κB activity which is required to prevent BV cytotoxicity. In line with these results, the RNA-seq analysis of the BV-resistant single-cell clones demonstrated a consistent upregulation of NF-κB signature genes, as well as the ABC transporter gene ABCB1. Mechanically, NF-κB regulates BV treatment sensitivity through mediating ABCB1 expression. Targeting NF-κB activity synergized well with BV in killing Hodgkin lymphoma cell lines, augmented BV sensitivity, and overcame BV resistance in vitro and in Hodgkin lymphoma xenograft mouse models. CONCLUSIONS: Our identification of this previously unrecognized mechanism provides novel knowledge of possible BV responsiveness and resistance mechanisms in Hodgkin lymphoma, as well as leads to promising hypotheses for the development of therapeutic strategies to overcome BV resistance in this disease.

Disruption of Thrombocyte and T Lymphocyte Development by a Mutation in ARPC1B.

Regulation of the actin cytoskeleton is crucial for normal development and function of the immune system, as evidenced by the severe immune abnormalities exhibited by patients bearing inactivating mutations in the Wiskott-Aldrich syndrome protein (WASP), a key regulator of actin dynamics. WASP exerts its effects on actin dynamics through a multisubunit complex termed Arp2/3. Despite the critical role played by Arp2/3 as an effector of WASP-mediated control over actin polymerization, mutations in protein components of the Arp2/3 complex had not previously been identified as a cause of immunodeficiency. Here, we describe two brothers with hematopoietic and immunologic symptoms reminiscent of Wiskott-Aldrich syndrome (WAS). However, these patients lacked mutations in any of the genes previously associated with WAS. Whole-exome sequencing revealed a homozygous 2 bp deletion, n.c.G623DEL-TC (p.V208VfsX20), in Arp2/3 complex component ARPC1B that causes a frame shift resulting in premature termination. Modeling of the disease in zebrafish revealed that ARPC1B plays a critical role in supporting T cell and thrombocyte development. Moreover, the defects in development caused by ARPC1B loss could be rescued by the intact human ARPC1B ortholog, but not by the p.V208VfsX20 variant identified in the patients. Moreover, we found that the expression of ARPC1B is restricted to hematopoietic cells, potentially explaining why a mutation in ARPC1B has now been observed as a cause of WAS, whereas mutations in other, more widely expressed, components of the Arp2/3 complex have not been observed.