Search Results (38)

Predominantly antibody deficiencies (PADs) are the most prevalent types of inherited errors of immunity (IEI) and are characterized by a broad range of clinical manifestations, such as recurrent infections, autoimmunity, lymphoproliferation, atopy and malignancy. The aim of this study was to identify genetic defects associated with PADs in order to improve diagnosis and personalized care. Twenty patients (male/female: 12/8, median age of disease onset: 16.5 years, range: 1–50) were analyzed by next-generation sequencing (NGS) using a custom panel of 30 genes associated with PADs and their possible disease phenotype. The detected variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and inheritance, and the penetrance patterns were evaluated by PCR–Sanger sequencing. Novel and rare mutations associated with the phenotype of common variable immunodeficiency (CVID) in genes encoding the transcription factors NFKB1, NFKB2 and IKZF1/IKAROS were identified. Alphafold3 protein structure prediction was utilized to perform a comprehensive visualization strategy and further delineate the mutation-bearing domains and elucidate their potential impact on protein function. This study highlights the value of genetic testing in PADs and will guide further research and improvement in diagnosis and treatment. Full article

Several etiologic factors for the development of acute leukemias have been suggested; however, none is applicable to all cases. We isolated a certain mycovirus-containing Aspergillus flavus (MCAF) from the home of a patient with acute lymphoblastic leukemia. Repeated electron microscopic evaluations proved the existence of mycovirus in this organism. According to chemical analysis, this organism does not produce any aflatoxin, possibly due to its infestation with mycoviruses. We reported that using the ELISA technique, forty pediatric patients with acute lymphoblastic leukemia (ALL) uniformly had antibodies to the products of MCAF. In contrast, three separate groups of controls, consisting of normal blood donors, individuals with solid tumors, and patients with sickle cell disease, were negative. In vitro exposure of mononuclear blood cells from patients with ALL, in full remission, to the products of MCAF induced redevelopment of cell surface phenotypes and genetic markers characteristic of ALL. The controls were negative. The incubation of normal and ALL cell lines with the products of MCAF resulted in significant cellular apoptosis, changes in the cell cycle, and the downregulation of transcription factors, including PAX-5 and Ikaros (75 and 55 kDa). Fungi are widespread in nature, and many contain mycoviruses. Normally, an individual inhales 1 to 10 fungal spores per minute, while farmers can inhale up to 75,000 spores per minute. It is known that farmers and foresters, who are more exposed to fungi, have a higher rate of acute leukemia. In contrast, asthmatics, most of whom are allergic to fungal agents, and individuals working in office settings have a lower rate. One of the theories for the development of acute leukemia suggests a genetic predisposition followed by exposure to an infectious agent. With the above findings, we propose that mycovirus-containing Aspergillus flavus may have an etiological role in leukemogenesis in immune-depressed and genetically susceptible individuals. Full article

Transcription factors control genes to maintain normal hemopoiesis, and dysregulation of some factors can lead to acute lymphoblastic leukemia (ALL). Mycoviruses are known to alter the genetics of their fungal host. The present study evaluates the effects of the products of a mycovirus-containing Aspergillus flavus (MCAF), isolated from the home of a patient with ALL, on certain transcription factors of normal and ALL cell lines. Our published studies have shown that ALL patients have antibodies to MCAF, and that exposure of the mononuclear leukocytes of patients in complete remission to its products, unlike controls, results in the re-development of genetic and cell surface phenotypes characteristic of ALL. For the present study, normal, pre-B, and B-cell leukemia cell lines were exposed to the culture of MCAF. Pre- and post-exposure levels of PAX5, Ikaros, and NF-κB were assessed. Exposure to MCAF resulted in apoptosis, cell cycle changes, and complete downregulation of all transcription factors in normal cell lines. In acute leukemia cell lines, cellular apoptosis and alterations in the cell cycle were also noted; however, while there was downregulation of all tested transcription factors, residual levels were retained. The noted alterations in the transcription factors caused by MCAF are novel findings. The possible role of MCAF in leukemogenesis needs to be further investigated. Mycovirus-containing Aspergillus flavus was initially isolated from a leukemia patient’s home. Our prior published studies have illuminated intriguing associations of this organism with leukemia. Unlike controls, patients diagnosed with acute lymphoblastic leukemia (ALL) harbor antibodies to this organism. Furthermore, the exposure of mononuclear cells from patients with ALL in complete remission to the products of this organism reproduced genetic and cell phenotypes characteristic of ALL. These findings underscore the potential role of environmental factors in leukemogenesis and hint at novel avenues for therapeutic intervention and preventive strategies. Full article

The Ikaros zinc finger factor 1 is a transcription factor with a well-known role in B- and T-cell development. The deletions of IKZF1 have an established significance in acute lymphoblastic leukemia, while reports on its prevalence and prognostic significance among ALL subtypes and regions vary. Breakpoint-specific qPCR is a practical method for testing of the most frequent types of IKZF1 deletions, considering there is clustering of the deletion events. The most commonly reported deletions are Δ4–7, Δ4–8, Δ2–7, and Δ2–8, with deletion Δ4–7 being the most common one. We retrospectively administered a breakpoint-specific qPCR design for screening for the most frequent types of IKZF1 deletions to 78 ALL patients that were diagnosed and treated between 2010 and 2022. We observed the products through gel electrophoresis, and we conducted descriptive statistics, EFS, and OS analyses. Our study found 19 patients with IKZF1 deletions, with two subjects manifesting more than one deletion. The prevalence in the different subgroups was as follows: Ph/+/ B-ALL 46%, Ph/−/ B-ALL 30%, T-ALL/LBL 4%. There was a statistically significant difference in EFS of 39 vs. 0% in favor of patients without deletions (p = 0.000), which translated to a difference in OS of 49 vs. 0% (p = 0.001). This difference was preserved in the subgroup of Ph/−/ B-ALL, while there was no significant difference in the Ph/+/ B-ALL. The most frequently observed type of deletion (15 out of 19) was the Δ4–7. There is a strong negative prognostic impact of the IKZF1 deletions at diagnosis in the observed population. IKZF1 deletion testing through breakpoint-specific qPCR is a practical approach in diagnostic testing for this risk factor. IKZF1 deletions may warrant treatment decisions and intensified treatment strategies to overcome the negative prognostic impact. Full article

Progress in the treatment of multiple myeloma (MM) has resulted in improvement in the survival rate. However, there is still a need for more efficacious and tolerated therapies. We and others have shown that bromodomain-containing protein 9 (BRD9), a member of the non-canonical SWI/SNF chromatin remodeling complex, plays a role in MM cell survival, and targeting BRD9 selectively blocks MM cell proliferation and synergizes with IMiDs. We found that synergy in vitro is associated with the downregulation of MYC and Ikaros proteins, including IKZF3, and overexpression of IKZF3 or MYC could partially reverse synergy. RNA-seq analysis revealed synergy to be associated with the suppression of pathways associated with MYC and E2F target genes and pathways, including cell cycle, cell division, and DNA replication. Stimulated pathways included cell adhesion and immune and inflammatory response. Importantly, combining IMiD treatment and BRD9 targeting, which leads to the downregulation of MYC protein and upregulation of CRBN protein, was able to override IMiD resistance of cells exposed to iberdomide in long-term culture. Taken together, our results support the notion that combination therapy based on agents targeting BRD9 and IKZF3, two established dependencies in MM, represents a promising novel therapeutic strategy for MM and IMiD-resistant disease. Full article

Mezigomide is an oral cereblon E3 ligase modulator (CELMoD) that is under clinical investigation in patients with relapsed/refractory (RR) multiple myeloma (MM). Like other CELMoD compounds, mezigdomide acts by altering the conformation of cereblon within the cullin 4A ring ligase–cereblon (CRL4CRBN) E3 ubiquitin ligase complex, thereby recruiting novel protein substrates for selective proteasomal degradation. These include two critical lymphoid transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), also known as Ikaros and Aiolos, which have important roles in the development and differentiation of hematopoietic cells, in MM pathobiology, and in suppressing the expression of interferon-stimulating genes and T-cell stimulation. Among the CELMoDs, mezigdomide has the greatest cereblon-binding potency, plus the greatest potency for the degradation of Ikaros and Aiolos and subsequent downstream antimyeloma effects. Preclinical studies of mezigdomide have demonstrated its anti-proliferative and apoptotic effects in MM, along with its immune-stimulatory effects and its synergistic activity with other antimyeloma agents, including in lenalidomide-/pomalidomide-resistant MM cell lines and mouse xenograft models. Early-phase clinical trial data indicate notable activity in heavily pretreated patients with RRMM, including those with triple-class-refractory disease, together with a tolerable and manageable safety profile. This review summarizes current preclinical and clinical findings with mezigdomide and its potential future roles in the treatment of MM. Full article

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by a specific expansion of mature B-cell clones. We hypothesized that the disease has a heterogeneous clinical outcome that depends on the genes and signaling pathways active in the malignant clone of the individual patient. It was found that several signaling pathways are active in CLL, namely, NOTCH1, the Ikaros family genes, BCL2, and NF-κB, all of which contribute to cell survival and the proliferation of the leukemic clone. Therefore, we analyzed primary CLL cells for the gene and protein expression of NOTCH1, DELTEX1, HES1, and AIOLOS in both peripheral blood lymphocytes (PBLs) and the bone marrow (BM) of patients, as well as the expression of BCL2 and miRNAs to see if they correlate with any of these genes. BCL2 and AIOLOS were highly expressed in all CLL samples as previously described, but we show here for the first time that AIOLOS expression was higher in the PBLs than in the BM. On the other hand, NOTCH1 activation was higher in the BM. In addition, miR-15a, miR-181, and miR-146 were decreased and miR-155 had increased expression in most samples. The activation of the NOTCH pathway in vitro increases the susceptibility of primary CLL cells to apoptosis despite high BCL2 expression. Full article

IKZF1 encodes the transcription factor IKAROS, a zinc finger DNA-binding protein with a key role in lymphoid lineage development. IKAROS plays a critical role in the development of lineage-restricted mature lymphocytes. Deletions within IKZF1 in B-cell acute lymphoblastic leukemia (B-ALL) lead to a loss of normal IKAROS function, conferring leukemic stem cell properties, including self-renewal and subsequent uncontrolled growth. IKZF1 deletions are associated with treatment resistance and inferior outcomes. Early identification of IKZF1 deletions in B-ALL may inform the intensification of therapy and other potential treatment strategies to improve outcomes in this high-risk leukemia. Full article

The Helios protein (encoded by the IKZF2 gene) is a member of the Ikaros transcription family and it has recently been proposed as a promising biomarker for systemic lupus erythematosus (SLE) disease progression in both mouse models and patients. Helios is beginning to be studied extensively for its influence on the T regulatory (Treg) compartment, both CD4⁺ Tregs and KIR⁺/Ly49⁺ CD8⁺ Tregs, with alterations to the number and function of these cells correlated to the autoimmune phenomenon. This review analyzes the most recent research on Helios expression in relation to the main immune cell populations and its role in SLE immune homeostasis, specifically focusing on the interaction between T cells and tolerogenic dendritic cells (tolDCs). This information could be potentially useful in the design of new therapies, with a particular focus on transfer therapies using immunosuppressive cells. Finally, we will discuss the possibility of using nanotechnology for magnetic targeting to overcome some of the obstacles related to these therapeutic approaches. Full article

One key process that controls leukemogenesis is the regulation of oncogenic gene expression by transcription factors acting as tumor suppressors. Understanding this intricate mechanism is crucial to elucidating leukemia pathophysiology and discovering new targeted treatments. In this review, we make a brief overview of the physiological role of IKAROS and the molecular pathway that contributes to acute leukemia pathogenesis through IKZF1 gene lesions. IKAROS is a zinc finger transcription factor of the Krüppel family that acts as the main character during hematopoiesis and leukemogenesis. It can activate or repress tumor suppressors or oncogenes, regulating the survival and proliferation of leukemic cells. More than 70% of Ph+ and Ph-like cases of acute lymphoblastic leukemia exhibit IKZF1 gene variants, which are linked to worse treatment outcomes in both childhood and adult B-cell precursor acute lymphoblastic leukemia. In the last few years, much evidence supporting IKAROS involvement in myeloid differentiation has been reported, suggesting that loss of IKZF1 might also be a determinant of oncogenesis in acute myeloid leukemia. Considering the complicated “social” network that IKAROS manages in hematopoietic cells, we aim to focus on its involvement and the numerous alterations of molecular pathways it can support in acute leukemias. Full article

Artificial intelligence (AI) can identify actionable oncology biomarkers. This research integrates our previous analyses of non-Hodgkin lymphoma. We used gene expression and immunohistochemical data, focusing on the immune checkpoint, and added a new analysis of macrophages, including 3D rendering. The AI comprised machine learning (C5, Bayesian network, C&R, CHAID, discriminant analysis, KNN, logistic regression, LSVM, Quest, random forest, random trees, SVM, tree-AS, and XGBoost linear and tree) and artificial neural networks (multilayer perceptron and radial basis function). The series included chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, Burkitt, diffuse large B-cell lymphoma, marginal zone lymphoma, and multiple myeloma, as well as acute myeloid leukemia and pan-cancer series. AI classified lymphoma subtypes and predicted overall survival accurately. Oncogenes and tumor suppressor genes were highlighted (MYC, BCL2, and TP53), along with immune microenvironment markers of tumor-associated macrophages (M2-like TAMs), T-cells and regulatory T lymphocytes (Tregs) (CD68, CD163, MARCO, CSF1R, CSF1, PD-L1/CD274, SIRPA, CD85A/LILRB3, CD47, IL10, TNFRSF14/HVEM, TNFAIP8, IKAROS, STAT3, NFKB, MAPK, PD-1/PDCD1, BTLA, and FOXP3), apoptosis (BCL2, CASP3, CASP8, PARP, and pathway-related MDM2, E2F1, CDK6, MYB, and LMO2), and metabolism (ENO3, GGA3). In conclusion, AI with immuno-oncology markers is a powerful predictive tool. Additionally, a review of recent literature was made. Full article

The hematopoietic transcription factor Ikaros (IKZF1) regulates normal B cell development and functions as a tumor suppressor in precursor B cell acute lymphoblastic leukemia (B-ALL). MicroRNAs (miRNAs) are small regulatory RNAs that through post-transcriptional gene regulation play critical roles in intracellular processes including cell growth in cancer. However, the role of Ikaros in the regulation of miRNA expression in developing B cells is unknown. In this study, we examined the Ikaros-regulated miRNA targets using human IKZF1-mutated Ph⁺ B-ALL cell lines. Inducible expression of wild-type Ikaros (the Ik1 isoform) caused B-ALL growth arrest and exit from the cell cycle. Global miRNA expression analysis revealed a total of 31 miRNAs regulated by IK1, and ChIP-seq analysis showed that Ikaros bound to several Ik1-responsive miRNA genes. Examination of the prognostic significance of miRNA expression in B-ALL indicate that the IK1-regulated miRNAs hsa-miR-26b, hsa-miR-130b and hsa-miR-4649 are significantly associated with outcome in B-ALL. Our findings establish a potential regulatory circuit between the tumor-suppressor Ikaros and the oncogenic miRNA networks in IKZF1-mutated B-ALL. These results indicate that Ikaros regulates the expression of a subset of miRNAs, of which several may contribute to B-ALL growth. Full article

Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders. They lower the generation of proinflammatory cytokines, particularly TNF-α which is pivotal in microglial cell activation. Unfortunately, thalidomide-like drugs possess adverse effects in humans before achieving anti-inflammatory drug levels. We developed F-3,6′-dithiopomalidomide (F-3,6′-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6′-DP binds to cereblon but does not efficiently trigger the degradation of the transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses of thalidomide-like drugs. We utilized a phenotypic drug discovery approach that employed cellular and animal models in the selection and development of F-3,6’-DP. F-3,6′-DP significantly mitigated LPS-induced inflammatory markers in RAW 264.7 cells, and lowered proinflammatory cytokine/chemokine levels in the plasma and brain of rats challenged with systemic LPS. We subsequently examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) in mice, a model of moderate TBI known to induce inflammation. F-3,6′-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6′-DP represents a novel class of thalidomide-like drugs that do not lower classical cereblon-associated transcription factors but retain anti-inflammatory actions and possess efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders. Full article

Multiple myeloma (MM) is a malignant plasma cell (PC) neoplasm, which also displays pathological bone involvement. Clonal expansion of MM cells in the bone marrow causes a perturbation of bone homeostasis that culminates in MM-associated bone disease (MMABD). We previously demonstrated that the S/T kinase CK1α sustains MM cell survival through the activation of AKT and β-catenin signaling. CK1α is a negative regulator of the Wnt/β-catenin cascade, the activation of which promotes osteogenesis by directly stimulating the expression of RUNX2, the master gene regulator of osteoblastogenesis. In this study, we investigated the role of CK1α in the osteoblastogenic potential of mesenchymal stromal cells (MSCs) and its involvement in MM–MSC cross-talk. We found that CK1α silencing in in vitro co-cultures of MMs and MSCs modulated RUNX2 expression differently in PCs and in MSCs, mainly through the regulation of Wnt/β-catenin signaling. Our findings suggest that the CK1α/RUNX2 axis could be a potential therapeutic target for constraining malignant PC expansion and supporting the osteoblastic transcriptional program of MSCs, with potential for ameliorating MMABD. Moreover, considering that Lenalidomide treatment leads to MM cell death through Ikaros, Aiolos and CK1α proteasomal degradation, we examined its effects on the osteoblastogenic potential of MSC compartments. Full article

This article describes the ocular phenotype associated with the identified Casitas B-lineage lymphoma (CBL) gene mutation and reviews the current literature. This work also includes the longitudinal follow-up of five unrelated cases of unexplained fundus lesions with visual loss associated with a history of hepatosplenomegaly. Wide repeated workup was made to rule out infections, inflammatory diseases, and lysosomal diseases. No variants in genes associated with retinitis pigmentosa, cone–rod dystrophy, and inherited optic neuropathy were found. Molecular analysis was made using next-generation sequencing (NGS) and whole-exome sequencing (WES). The results included two cases sharing ophthalmological signs including chronic macular edema, vascular leakage, visual field narrowing, and electroretinography alteration. Two other cases showed damage to the optic nerve head and a fifth young patient exhibited bilateral complicated vitreoretinal traction and carried a heterozygous mutation in the CBL gene associated with a mutation in the IKAROS gene. Ruxolitinib as a treatment for RASopathy did not improve eye conditions, whereas systemic lesions were resolved in one patient. Mutations in the CBL gene were found in all five cases. In conclusion, a detailed description may pave the way for the CBL mutation ocular phenotype. Genetic analysis using whole-exome sequencing could be useful in the diagnosis of unusual clinical features. Full article