TLE3 Is a Novel Fusion Partner of JAK2 in Myeloid/Lymphoid Neoplasm With Eosinophilia Responding to JAK2 Inhibition.

Chromosomal rearrangements involving Janus kinase 2 (JAK2) are rare but recurrent findings in lymphoid or myeloid neoplasia. Detection of JAK2 fusion genes is important as patients with aberrantly activated JAK2 may benefit from treatment with tyrosine kinase inhibitors such as ruxolitinib. Here, we report a novel fusion gene between the transcriptional co-repressor-encoding gene transducin-like enhancer of split 3 (TLE3) and JAK2 in a patient initially diagnosed with chronic eosinophilic leukemia with additional mutations in PTPN11 and NRAS. The patient was successfully treated with the JAK2 inhibitor ruxolitinib for 8 months before additional somatic mutations were acquired and the disease progressed into an acute lymphoblastic T-cell leukemia/lymphoma. The present case shows similarities to previously reported cases with PCM1::JAK2 and BCR::JAK2 with regard to disease phenotype and response to ruxolitinib, and importantly, provides an example that also patients harboring other JAK2 fusion genes may benefit from treatment with JAK2 inhibitors.

Myeloproliferative neoplasm with eosinophilia and coexisting BCR::ABL1 and PDGFRB rearrangement: favorable and rapid response to imatinib.

Here, we present a rare case of myeloproliferative neoplasms (MPN) with eosinophilia harboring both BCR::ABL1 and PDGFRB rearrangements, posing a classification dilemma. The patient exhibited clinical and laboratory features suggestive of chronic myeloid leukemia (CML) and myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), highlighting the diagnostic challenges associated with overlapping phenotypes. Despite the complexity, imatinib treatment swiftly achieved deep molecular remission, underscoring the therapeutic efficacy of tyrosine kinase inhibitors in such scenarios. Furthermore, the rapid attainment of deep remission by this patient in response to imatinib closely resembles that observed in MLN-TK patients with PDGFRB rearrangements. Further research is warranted to elucidate the underlying mechanisms driving the coexistence of multiple oncogenic rearrangements in MPNs and to optimize therapeutic strategies for these complex cases.

A term infant with severe hypereosinophilia secondary to CMV infection and the STAT1 gene mutation: a case report : List of authors.

Hypereosinophilia is a rare presentation in all age groups, particularly when it is severe, persistent, and progressive. We describe the clinical characteristics and course of severe hypereosinophilia in a full-term Saudi female neonate. A febrile respiratory illness evolved with a progressive increase in peripheral blood leukocyte and eosinophil counts, reaching 44.9% of leukocytes and an absolute value of 57,000 cells/µl. Different etiological examinations (for viral, bacterial, immunodeficiency, hyper IgE syndrome, gene mutations) revealed extremely high CMV antigenemia and a homozygous mutation in the STAT1 gene. Anhelation was relieved by oxygen and anti-viral treatment. Steroids brought a dramatic response in peripheral blood counts within 24 h. After a 6-week course of antiviral and steroid treatment at home, she had an excellent general condition. Conclusion: Although a rare pathology, it is important to consider genetic disorders when there is an atypical immune response to viral infections.

Fifth Edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues: Acute Lymphoblastic Leukemias, Mixed-Phenotype Acute Leukemias, Myeloid/Lymphoid Neoplasms With Eosinophilia, Dendritic/Histiocytic Neoplasms, and Genetic Tumor Syndromes.

This manuscript represents a review of lymphoblastic leukemia/lymphoma (acute lymphoblastic leukemia/lymphoblastic lymphoma), acute leukemias of ambiguous lineage, mixed-phenotype acute leukemias, myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangements, histiocytic and dendritic neoplasms, and genetic tumor syndromes of the 5th edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The diagnostic, clinicopathologic, cytogenetic, and molecular genetic features are discussed. The differences in comparison to the 4th revised edition of the World Health Organization classification of hematolymphoid neoplasms are highlighted.

Muscle eosinophilia is a hallmark of chronic disease in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy caused by the aberrant increased expression of the DUX4 retrogene in skeletal muscle cells. The DUX4 gene encodes a transcription factor that functions in zygotic genome activation and then is silenced in most adult somatic tissues. DUX4 expression in FSHD disrupts normal muscle cell function; however, the downstream pathogenic mechanisms are still unclear. Histologically, FSHD affected muscles show a characteristic dystrophic phenotype that is often accompanied by a pronounced immune cell infiltration, but the role of the immune system in FSHD is not understood. Previously, we used ACTA1;FLExDUX4 FSHD-like mouse models varying in severity as discovery tools to identify increased Interleukin 6 and microRNA-206 levels as serum biomarkers for FSHD disease severity. In this study, we use the ACTA1;FLExDUX4 chronic FSHD-like mouse model to provide insight into the immune response to DUX4 expression in skeletal muscles. We demonstrate that these FSHD-like muscles are enriched with the chemoattractant eotaxin and the cytotoxic eosinophil peroxidase, and exhibit muscle eosinophilia. We further identified muscle fibers with positive staining for eosinophil peroxidase in human FSHD muscle. Our data supports that skeletal muscle eosinophilia is a hallmark of FSHD pathology.

Quantification of eosinophilic area and its potential molecular feature in clear cell renal cell carcinoma.

OBJECTIVE: Previous studies have acknowledged the presence of eosinophilic cytoplasm in clear cell renal cell carcinoma, yet the precise quantification method and potential molecular attributes in clear cell renal cell carcinoma remain elusive. This study endeavours to precisely quantify the eosinophilic attribute and probe into the molecular mechanisms governing its presence in clear cell renal cell carcinoma. METHODS: Data from cohorts of clear cell renal cell carcinoma patients who underwent nephrectomy, comprising The Cancer Genome Atlas cohort (n = 475) and Sun Yat-sen University Cancer Center cohort (n = 480), were aggregated to assess the eosinophilic attribute. Additionally, Omics data from Clinical Proteomic Tumor Analysis Consortium (CPTAC) (n = 58) were leveraged to explore the potential molecular features associated with eosinophilic clear cell renal cell carcinoma. Employing receiver operating characteristic curve analysis, the proportion of tumour cells with eosinophilic cytoplasm was determined, leading to the classification of each cohort into distinct groups: a clear group (<5%) and an eosinophilic group (≥5%). RESULTS: In both cohorts, the eosinophilic feature consistently correlated with higher International Society of Urological Pathology (ISUP) grade, elevated tumor stage, and the presence of necrosis. Furthermore, the Kaplan-Meier method demonstrated that patients in the eosinophilic group exhibited shorter overall survival or disease-free survival compared with those in the clear group, a pattern reaffirmed in various stratified survival analyses. Intriguingly, within The Cancer Genome Atlas cohort, the pathological characterization of cell cytoplasm (eosinophilic vs. clear) emerged as an independent risk factor for overall survival (hazard ratio = 2.507 [95% confidence interval: 1.328-4.733], P = 0.005) or disease-free survival (hazard ratio = 1.730 [95% confidence interval: 1.062-2.818], P = 0.028) via Cox regression analysis. Moreover, multi-Omics data unveiled frequent BAP1 mutations and down-regulation of Erythroblast Transformation-Specific-Related Gene associated with the eosinophilic feature in clear cell renal cell carcinoma. Additionally, patients with low expression of Erythroblast Transformation-Specific-Related Gene showed worse overall survival (P < 0.001). CONCLUSIONS: The quantification of the eosinophilic feature serves as a robust predictor of clinical prognosis in clear cell renal cell carcinoma. Furthermore, the manifestation of this feature may be linked to BAP1 mutations and the down-regulation of Erythroblast Transformation-Specific-Related Gene in clear cell renal cell carcinoma. Significantly, the expression levels of Erythroblast Transformation-Specific-Related Gene manifest as an exemplary prognostic marker, providing exceptional predictive accuracy for the clinical prognosis in clear cell renal cell carcinoma.

ETV6::ACSL6 translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression.

ETV6::ACSL6 represents a rare genetic aberration in hematopoietic neoplasms and is often associated with severe eosinophilia, which confers an unfavorable prognosis requiring additional anti-inflammatory treatment. However, since the translocation is unlikely to produce a fusion protein, the mechanism of ETV6::ACSL6 action remains unclear. Here, we performed multi-omics analyses of primary leukemia cells and patient-derived xenografts from an acute lymphoblastic leukemia (ALL) patient with ETV6::ACSL6 translocation. We identified a super-enhancer located within the ETV6 gene locus, and revealed translocation and activation of the super-enhancer associated with the ETV6::ACSL6 fusion. The translocated super-enhancer exhibited intense interactions with genomic regions adjacent to and distal from the breakpoint at chromosomes 5 and 12, including genes coding inflammatory factors such as IL-3. This led to modulations in DNA methylation, histone modifications, and chromatin structures, triggering transcription of inflammatory factors leading to eosinophilia. Furthermore, the bromodomain and extraterminal domain (BET) inhibitor synergized with standard-of-care drugs for ALL, effectively reducing IL-3 expression and inhibiting ETV6::ACSL6 ALL growth in vitro and in vivo. Overall, our study revealed for the first time a cis-regulatory mechanism of super-enhancer translocation in ETV6::ACSL6ALL, leading to an ALL-accompanying clinical syndrome. These findings may stimulate novel treatment approaches for this challenging ALL subtype.

Acute leukemia with cytogenetically cryptic FGFR1 rearrangement and lineage switch during therapy: A case report and literature review.

OBJECTIVES: Myeloid/lymphoid neoplasms with FGFR1 rearrangement are a rare group of neoplasms that share features of eosinophilia and lineage promiscuity. First, we described a challenging case of acute leukemia with lineage switch and cytogenetically cryptic FGFR1. Second, we aimed to systemically review this phenomenon in published literature. METHODS: A 68-year-old man with a history of chemotherapy exposure presented with acute leukemia of myeloid lineage without eosinophilia or 8p11 abnormalities on karyotyping. Over a refractory and relapsing course, the blast phenotype shifted to B lymphoid. RESULTS: Fluorescence in situ hybridization identified a cytogenetically cryptic FGFR1 rearrangement, likely a paracentric inversion. We identified 26 published cases of FGFR1-rearranged acute leukemia with ambiguous, mixed, or switching lineage. Although there was variability in the partner gene, anatomical location of different phenotypes, and timing of lineage switch, the prognosis was consistently poor in the absence of novel therapy. CONCLUSIONS: Ours is the only reported case of FGFR1-rearranged neoplasms with a disease sequence of acute myeloid leukemia transforming to B-cell acute lymphoblastic leukemia and 1 of only 3 reported cases with cytogenetically cryptic FGFR1 rearrangement. Fluorescence in situ hybridization testing for FGFR1 rearrangement should be a standard investigation in leukemia of mixed or switching lineage.

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes: A workshop report with focus on novel entities and a literature review including paediatric cases.

Myeloid/lymphoid neoplasms with eosinophilia (M/LN-eo) and tyrosine kinase (TK) gene fusions are a rare group of haematopoietic neoplasms with a broad range of clinical and morphological presentations. Paediatric cases have increasingly been recognised. Importantly, not all appear as a chronic myeloid neoplasm and eosinophilia is not always present. In addition, standard cytogenetic and molecular methods may not be sufficient to diagnose M/LN-eo due to cytogenetically cryptic aberrations. Therefore, additional evaluation with fluorescence in-situ hybridisation and other molecular genetic techniques (array-based comparative genomic hybridisation, RNA sequencing) are recommended for the identification of specific TK gene fusions. M/LN-eo with JAK2 and FLT3-rearrangements and ETV6::ABL1 fusion were recently added as a formal member to this category in the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In addition, other less common defined genetic alterations involving TK genes have been described. This study is an update on M/LN-eo with TK gene fusions with focus on novel entities, as illustrated by cases submitted to the Bone Marrow Workshop, organised by the European Bone Marrow Working Group (EBMWG) within the frame of the 21st European Association for Haematopathology congress (EAHP-SH) in Florence 2022. A literature review was performed including paediatric cases of M/LN-eo with TK gene fusions.

Sustained Response to Ruxolitinib of Eosinophilia-Associated Myeloproliferative Neoplasm with Translocation t(8;9)(p21;p24).

The translocation t(8;9) produces the fusion gene PCM1-JAK2, resulting in the continuous activation of the JAK2 tyrosine kinase. Myelodysplastic/myeloproliferative neoplasms are the most common disease with t(8;9)/PCM1-JAK2. Individuals with this abnormality have similar features, and JAK2 kinase inhibitor (ruxolitinib) is an effective treatment of the condition. The long-term remission results of ruxolitinib are varied. It is important to determine the response to ruxolitinib. Here, we describe a patient who has been diagnosed with eosinophilia-associated myeloproliferative neoplasm with t(8;9)(p21;p24). This patient has achieved sustained response for >1 year since the administration of ruxolitinib.

Role of SNAP25 on the occurrence and development of eosinophilic gastritis.

Eosinophilic gastritis is characterized by gastrointestinal symptoms accompanied by peripheral eosinophilia. This study aims to explore the association between eosinophilic gastritis and Synaptosome Associated Protein 25 (SNAP25), and provide a new direction for the diagnosis and treatment of eosinophilic gastritis. GSE54043 was downloaded from the gene expression omnibus database. Differentially expressed genes (DEGs) were screened. The functions of common DEGs were annotated by Database for Annotation, Visualization and Integrated Discovery and Metascape. The protein-protein interaction network of common DEGs was obtained by Search Tool for the Retrieval of Interacting Genes and visualized by Cytoscape. Significant modules were identified from the protein-protein interaction network. A total of 186 patients with eosinophilic gastritis were recruited. The clinical data were recorded and the expression levels of CPE, SST, PCSK2, SNAP25, and SYT4 were detected. Pearson chi-square test and Spearman correlation coefficient were used to analyze the relationship between eosinophilic gastritis and related parameters. Univariate and multivariate Logistic regression were used for further analysis. 353 DEGs were presented. The top 10 genes screened by cytoHubb were shown, and Veen diagram figured out 5 mutual genes. Pearson's chi-square test showed that SNAP25 (P < .001) was significantly associated with eosinophilic gastritis. Spearman correlation coefficient showed a significant correlation between eosinophilic gastritis and SNAP25 (ρ = -0.569, P < .001). Univariate logistic regression analysis showed that SNAP25 (OR = 0.046, 95% CI: 0.018-0.116, P < .001) was significantly associated with eosinophilic gastritis. Multivariate logistic regression analysis showed that SNAP25 (OR = 0.024, 95% CI: 0.007-0.075, P < .001) was significantly associated with eosinophilic gastritis. The low expression of SNAP25 gene in eosinophilic gastritis is associated with a higher risk of eosinophilic gastritis.

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: reevaluation of the defining characteristics in a registry-based cohort.

In a registry-based analysis of 135 patients with "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-TK; FIP1L1::PDGFRA, n = 78; PDGFRB, diverse fusions, n = 26; FGFR1, diverse, n = 9; JAK2, diverse, n = 11; ETV6::ABL1, n = 11), we sought to evaluate the disease-defining characteristics. In 81/135 (60%) evaluable patients, hypereosinophilia (>1.5 × 109/l) was observed in 40/44 (91%) FIP1L1::PDGFRA and 7/7 (100%) ETV6::ABL1 positive patients but only in 13/30 (43%) patients with PDGFRB, FGFR1, and JAK2 fusion genes while 9/30 (30%) patients had no eosinophilia. Monocytosis >1 × 109/l was identified in 27/81 (33%) patients, most frequently in association with hypereosinophilia (23/27, 85%). Overall, a blast phase (BP) was diagnosed in 38/135 (28%) patients (myeloid, 61%; lymphoid, 39%), which was at extramedullary sites in 18 (47%) patients. The comparison between patients with PDGFRA/PDGFRB vs. FGFR1, JAK2, and ETV6::ABL1 fusion genes revealed a similar occurrence of primary BP (17/104, 16% vs. 8/31 26%, p = 0.32), a lower frequency (5/87, 6% vs. 8/23, 35%, p = 0.003) of and a later progression (median 87 vs. 19 months, p = 0.053) into secondary BP, and a better overall survival from diagnosis of BP (17.1 vs. 1.7 years, p < 0.0008). We conclude that hypereosinophilia with or without monocytosis and various phenotypes of BP occur at variable frequencies in MLN-TK.