Publications by authors named "Leticia Quintanilla-Martinez"

221 Publications

SOX11, CD70 and Treg cells configure the tumor immune microenvironment of aggressive mantle cell lymphoma.

Blood 2021 Jun 29. Epub 2021 Jun 29.

IDIBAPS, Barcelona, Spain.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a heterogeneous clinical and biological behavior. SOX11 oncogenic expression contributes to the aggressiveness of these tumors by different mechanisms including tumor and stromal cell interactions. However, the precise composition of the immune cell microenvironment of MCL, its possible relationship to SOX11 expression, and how it may contribute to tumor behavior is not well known. Here, we performed an integrative transcriptome analysis of 730 immune-related genes combined with the immune cell phenotype analysis by immunohistochemistry in SOX11+ and SOX11- primary nodal MCL cases and non-neoplastic reactive lymph nodes (RLN). SOX11+ MCL had a significant lower T-cell intratumoral infiltration compared to negative cases. A reduced expression of MHCI/II-like and T-cell costimulation and signaling activation related transcripts was significantly associated with poor clinical outcome. Moreover, we identified CD70 as a SOX11 direct target gene, whose overexpression was induced in SOX11+ but not SOX11- tumor cells by CD40L in vitro. CD70 was overexpressed in primary SOX11+ MCL and it was associated with an immune unbalance of the tumor microenvironment characterized by increased number of effector Treg cell infiltration, higher proliferation, and aggressive clinical course. CD27 was expressed with moderate to strong intensity in 76% of cases. Overall, our results suggest that SOX11 expression in MCL is associated with an immunosuppressive microenvironment characterized by CD70 overexpression in tumor cells, increased Treg cell infiltration and downmodulation of antigen-processing and -presentation and T-cell activation that could promote MCL progression and represent a potential target for tailored therapies.
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http://dx.doi.org/10.1182/blood.2020010527DOI Listing
June 2021

All activated signaling pathways lead to anaplastic large cell lymphoma (ALCL).

Leuk Lymphoma 2021 07 21;62(7):1541-1543. Epub 2021 May 21.

Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany.

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http://dx.doi.org/10.1080/10428194.2021.1924373DOI Listing
July 2021

Rapamycin delays allograft rejection in obese graft recipients through induction of myeloid-derived suppressor cells.

Immunol Lett 2021 Aug 17;236:1-11. Epub 2021 May 17.

Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany. Electronic address:

Obesity has become a relevant problem in transplantation medicine with steadily increasing numbers of obese graft recipients. However, the effect of immunomodulatory drugs on transplant-related outcomes among obese patients are unknown. Therefore, we evaluated the impact of rapamycin on allograft rejection and alloimmune response in a murine model of diet-induced obesity and fully-mismatched skin transplantation. Rapamycin significantly delayed allograft rejection in obese recipient mice compared to treated lean mice (14.5 days vs. 10.7 days, p = 0.005). Treatment with rapamycin increased frequencies of monocytic myeloid-derived suppressor cells (M-MDSCs), augmented the immunosuppressive activity of M-MDSCs on T cells through indoleamine 2,3-dioxygenase pathway and shifted CD4T cells towards regulatory T cells in obese graft recipients. In summary, our results demonstrate that rapamycin delays allograft rejection in obese graft recipients by enhancing suppressive immune cell function and shifting immune cell subsets towards anti-inflammatory conditions.
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http://dx.doi.org/10.1016/j.imlet.2021.05.003DOI Listing
August 2021

Burkitt lymphoma with a granulomatous reaction: an M1/Th1-polarised microenvironment is associated with controlled growth and spontaneous regression.

Histopathology 2021 May 5. Epub 2021 May 5.

Department of Medical Biotechnologies, University of Siena, Siena, Italy.

Aims: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously.

Methods And Results: All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein-Barr virus (EBV)-positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution.

Conclusions: Our data provide an in-vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self-limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV-positive BL patients in the era of cellular immunotherapy.
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http://dx.doi.org/10.1111/his.14391DOI Listing
May 2021

EBV and the Pathogenesis of NK/T Cell Lymphoma.

Cancers (Basel) 2021 Mar 19;13(6). Epub 2021 Mar 19.

Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, Eberhard-Karls-University, 72076 Tübingen, Germany.

Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus with tropism for B cells. EBV is linked to the pathogenesis of B cell, T cell and NK cell lymphoproliferations, with extranodal NK/T cell lymphoma, nasal type (ENKTCL) being the prototype of an EBV-driven lymphoma. ENKTCL is an aggressive neoplasm, particularly widespread in East Asia and the native population of Latin America, which suggests a strong genetic predisposition. The link between ENKTCL and different populations has been partially explored. EBV genome sequencing analysis recognized two types of strains and identified variants of the latent membrane protein 1 (LMP1), which revealed different oncogenic potential. In general, most ENKTCL patients carry EBV type A with LMP1 wild type, although the LMP1 variant with a 30 base pair deletion is also common, especially in the EBV type B, where it is necessary for oncogenic transformation. Contemporary high-throughput mutational analyses have discovered recurrent gene mutations leading to activation of the JAK-STAT pathway, and mutations in other genes such as and . The genomic landscape in ENKTCL highlights mechanisms of lymphomagenesis, such as immune response evasion, secondary to alterations in signaling pathways or epigenetics that directly or indirectly interfere with oncogenes or tumor suppressor genes. This overview discusses the most important findings of EBV pathogenesis and genetics in ENKTCL.
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http://dx.doi.org/10.3390/cancers13061414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003370PMC
March 2021

Fulminant mucormycosis during anti-leukemic treatment with blinatumomab in a child: A case report and review of the literature.

Med Mycol Case Rep 2021 Jun 29;32:4-9. Epub 2020 Dec 29.

University Children's Hospital Tuebingen, Department I - General Pediatrics, Hematology/Oncology, Hoppe-Seyler-Str.1, 72076, Tuebingen, Germany.

This is the first published case report of a child with acute lymphatic leukemia developing a fatal mucormycosis during blinatumomab treatment. The patient showed multiple, systemic thromboembolic lesions with ischemia, bleeding and infarction in almost all organs. The child succumbed to increased brain pressure resulting in cerebral herniation. This case particularly illustrates the fulminant progression and huge challenges of diagnosing and treating mucormycosis in children with hemato-oncological diseases during treatment with targeted therapeutic antibodies (blinatumomab).
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http://dx.doi.org/10.1016/j.mmcr.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806943PMC
June 2021

Machine learning identifies stroke features between species.

Theranostics 2021 1;11(6):3017-3034. Epub 2021 Jan 1.

Department of Neurology & Stroke, and Hertie Institute for Clinical Brain Research, Eberhard Karls University Tuebingen, Tuebingen, Germany.

Identification and localization of ischemic stroke (IS) lesions is routinely performed to confirm diagnosis, assess stroke severity, predict disability and plan rehabilitation strategies using magnetic resonance imaging (MRI). In basic research, stroke lesion segmentation is necessary to study complex peri-infarction tissue changes. Moreover, final stroke volume is a critical outcome evaluated in clinical and preclinical experiments to determine therapy or intervention success. Manual segmentations are performed but they require a specialized skill set, are prone to inter-observer variation, are not entirely objective and are often not supported by histology. The task is even more challenging when dealing with large multi-center datasets, multiple experimenters or large animal cohorts. On the other hand, current automatized segmentation approaches often lack histological validation, are not entirely user independent, are often based on single parameters, or in the case of complex machine learning methods, require vast training datasets and are prone to a lack of model interpretation. We induced IS using the middle cerebral artery occlusion model on two rat cohorts. We acquired apparent diffusion coefficient (ADC) and T2-weighted (T2W) images at 24 h and 1-week after IS induction. Subsets of the animals at 24 h and 1-week post IS were evaluated using histology and immunohistochemistry. Using a Gaussian mixture model, we segmented voxel-wise interactions between ADC and T2W parameters at 24 h using one of the rat cohorts. We then used these segmentation results to train a random forest classifier, which we applied to the second rat cohort. The algorithms' stroke segmentations were compared to manual stroke delineations, T2W and ADC thresholding methods and the final stroke segmentation at 1-week. Volume correlations to histology were also performed for every segmentation method. Metrics of success were calculated with respect to the final stroke volume. Finally, the trained random forest classifier was tested on a human dataset with a similar temporal stroke on-set. Manual segmentations, ADC and T2W thresholds were again used to evaluate and perform comparisons with the proposed algorithms' output. In preclinical rat data our framework significantly outperformed commonly applied automatized thresholding approaches and segmented stroke regions similarly to manual delineation. The framework predicted the localization of final stroke regions in 1-week post-stroke MRI with a median Dice similarity coefficient of 0.86, Matthew's correlation coefficient of 0.80 and false positive rate of 0.04. The predicted stroke volumes also strongly correlated with final histological stroke regions (Pearson correlation = 0.88, P < 0.0001). Lastly, the stroke region characteristics identified by our framework in rats also identified stroke lesions in human brains, largely outperforming thresholding approaches in stroke volume prediction (P<0.01). Our findings reveal that the segmentation produced by our proposed framework using 24 h MRI rat data strongly correlated with the final stroke volume, denoting a predictive effect. In addition, we show for the first time that the stroke imaging features can be directly translated between species, allowing identification of acute stroke in humans using the model trained on animal data. This discovery reduces the gap between the clinical and preclinical fields, unveiling a novel approach to directly co-analyze clinical and preclinical data. Such methods can provide further biological insights into human stroke and highlight the differences between species in order to help improve the experimental setups and animal models of the disease.
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http://dx.doi.org/10.7150/thno.51887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806470PMC
July 2021

Immunomodulatory role of reactive oxygen species and nitrogen species during T cell-driven neutrophil-enriched acute and chronic cutaneous delayed-type hypersensitivity reactions.

Theranostics 2021 1;11(2):470-490. Epub 2021 Jan 1.

Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important regulators of inflammation. The exact impact of ROS/RNS on cutaneous delayed-type hypersensitivity reaction (DTHR) is controversial. The aim of our study was to identify the dominant sources of ROS/RNS during acute and chronic trinitrochlorobenzene (TNCB)-induced cutaneous DTHR in mice with differently impaired ROS/RNS production. TNCB-sensitized wild-type, NADPH oxidase 2 (NOX2)- deficient (gp91), myeloperoxidase-deficient (MPO), and inducible nitric oxide synthase-deficient (iNOS) mice were challenged with TNCB on the right ear once to elicit acute DTHR and repetitively up to five times to induce chronic DTHR. We measured ear swelling responses and noninvasively assessed ROS/RNS production by employing the chemiluminescence optical imaging (OI) probe L-012. Additionally, we conducted extensive analyses of inflamed ears focusing on ROS/RNS production and the biochemical and morphological consequences. The L-012 OI of acute and chronic DTHR revealed completely abrogated ROS/RNS production in the ears of gp91 mice, up to 90 % decreased ROS/RNS production in the ears of MPO mice and unaffected ROS/RNS production in the ears of iNOS mice. The DHR flow cytometry analysis of leukocytes derived from the ears with acute DTHR confirmed our L-012 OI results. Nevertheless, we observed no significant differences in the ear swelling responses among all the experimental groups. The histopathological analysis of the ears of gp91 mice with acute DTHRs revealed slightly enhanced inflammation. In contrast, we observed a moderately reduced inflammatory immune response in the ears of gp91 mice with chronic DTHR, while the inflamed ears of MPO mice exhibited the strongest inflammation. Analyses of lipid peroxidation, 8-hydroxy-2'deoxyguanosine levels, redox related metabolites and genomic expression of antioxidant proteins revealed similar oxidative stress in all experimental groups. Furthermore, inflamed ears of wild-type and gp91 mice displayed neutrophil extracellular trap (NET) formation exclusively in acute but not chronic DTHR. MPO and NOX2 are the dominant sources of ROS/RNS in acute and chronic DTHR. Nevertheless, depletion of one primary source of ROS/RNS exhibited only marginal but conflicting impact on acute and chronic cutaneous DTHR. Thus, ROS/RNS are not a single entity, and each species has different properties at certain stages of the disease, resulting in different outcomes.
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http://dx.doi.org/10.7150/thno.51462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738859PMC
January 2021

Eosinophilia/Hypereosinophilia in the Setting of Reactive and Idiopathic Causes, Well-Defined Myeloid or Lymphoid Leukemias, or Germline Disorders.

Am J Clin Pathol 2021 02;155(2):179-210

Division of Hematopathology, Mayo Clinic, Rochester, MN.

Objectives: To report the findings of the 2019 Society for Hematopathology/European Association for Haematopathology Workshop within the categories of reactive eosinophilia, hypereosinophilic syndrome (HES), germline disorders with eosinophilia (GDE), and myeloid and lymphoid neoplasms associated with eosinophilia (excluding entities covered by other studies in this series).

Methods: The workshop panel reviewed 109 cases, assigned consensus diagnosis, and created diagnosis-specific sessions.

Results: The most frequent diagnosis was reactive eosinophilia (35), followed by acute leukemia (24). Myeloproliferative neoplasms (MPNs) received 17 submissions, including chronic eosinophilic leukemia, not otherwise specified (CEL, NOS). Myelodysplastic syndrome (MDS), MDS/MPN, and therapy-related myeloid neoplasms received 11, while GDE and HES received 12 and 11 submissions, respectively.

Conclusions: Hypereosinophilia and HES are defined by specific clinical and laboratory criteria. Eosinophilia is commonly reactive. An acute leukemic onset with eosinophilia may suggest core-binding factor acute myeloid leukemia, blast phase of chronic myeloid leukemia, BCR-ABL1-positive leukemia, or t(5;14) B-lymphoblastic leukemia. Eosinophilia is rare in MDS but common in MDS/MPN. CEL, NOS is a clinically aggressive MPN with eosinophilia as the dominant feature. Bone marrow morphology and cytogenetic and/or molecular clonality may distinguish CEL from HES. Molecular testing helps to better subclassify myeloid neoplasms with eosinophilia and to identify patients for targeted treatments.
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http://dx.doi.org/10.1093/ajcp/aqaa244DOI Listing
February 2021

Myeloid/Lymphoid Neoplasms Associated With Eosinophilia and Rearrangements of PDGFRA, PDGFRB, or FGFR1 or With PCM1-JAK2.

Am J Clin Pathol 2021 02;155(2):160-178

MD Anderson Cancer Center, Houston, TX.

Objectives: To summarize cases submitted to the 2019 Society for Hematopathology/European Association for Haematopathology Workshop under the category of myeloid/lymphoid neoplasms with eosinophilia and PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2 rearrangements, focusing on recent updates and relevant practice findings.

Methods: The cases were summarized according to their respective gene rearrangement to illustrate the spectrum of clinical, laboratory, and histopathology manifestations and to explore the appropriate molecular genetic tests.

Results: Disease presentations were heterogeneous, including myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDSs), MDS/MPN, acute myeloid leukemia, acute B- or T-lymphoblastic lymphoma/acute lymphoblastic lymphoma (ALL/LBL), or mixed-lineage neoplasms. Frequent extramedullary involvement occurred. Eosinophilia was common but not invariably present. With the advancement of RNA sequencing, cryptic rearrangements were recognized in genes other than PDGFRA. Additional somatic mutations were more frequent in the FGFR1-rearranged cases. Cases with B-ALL presentations differed from Philadelphia-like B-ALL by the presence of an underlying MPN. Cases with FLT3 and ABL1 rearrangements could be potential candidates for future inclusion in this category.

Conclusions: Accurate diagnosis and classification of this category of myeloid/lymphoid neoplasms has important therapeutic implications. With the large number of submitted cases, we expand our understanding of these rare neoplasms and improve our ability to diagnose these genetically defined disorders.
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http://dx.doi.org/10.1093/ajcp/aqaa208DOI Listing
February 2021

Reactive Eosinophil Proliferations in Tissue and the Lymphocytic Variant of Hypereosinophilic Syndrome.

Am J Clin Pathol 2021 02;155(2):211-238

Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany.

Objectives: The 2019 Society for Hematopathology and European Association for Haematopathology Workshop reviewed the spectrum of neoplastic, nonneoplastic, and borderline entities associated with reactive eosinophilia in tissue.

Methods: The workshop panel reviewed 46 cases covered in 2 workshop sessions.

Results: The 46 cases were presented with their consensus diagnoses during the workshop. Reactive eosinophilia in lymph nodes and other tissues may be accompanied by or be distinct from peripheral blood eosinophilia. Reactive etiologies included inflammatory disorders such as Kimura disease and IgG4-related disease, which may show overlapping pathologic features and reactions to infectious agents and hypersensitivity (covered in a separate review). Hodgkin, T-cell, and B-cell lymphomas and histiocytic neoplasms can result in reactive eosinophilia. The spectrum of these diseases is discussed and illustrated through representative cases.

Conclusions: Reactive eosinophilia in lymph nodes and tissues may be related to both nonneoplastic and neoplastic lymphoid proliferations and histiocytic and nonhematolymphoid processes. Understanding the differential diagnosis of reactive eosinophilia and the potential for overlapping clinical and pathologic findings is critical in reaching the correct diagnosis so that patients can be treated appropriately.
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http://dx.doi.org/10.1093/ajcp/aqaa227DOI Listing
February 2021

Comparative analysis of post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation reveals differences in the tumor microenvironment.

Virchows Arch 2021 Jun 15;478(6):1135-1148. Epub 2020 Dec 15.

Institute of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tuebingen, Liebermeisterstraße 8, 72076, Tuebingen, Germany.

Post-transplant lymphoproliferative disorders (PTLD) occur after solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HCT) and are frequently associated with Epstein-Barr virus (EBV). Because of the complex immune setup in PTLD patients, the tumor microenvironment (TME) is of particular interest to understand PTLD pathogenesis and elucidate predictive factors and possible treatment options. We present a comparative study of clinicopathological features of 48 PTLD after HCT (n = 26) or SOT (n = 22), including non-destructive (n = 6), polymorphic (n = 23), and monomorphic (n = 18) PTLD and classic Hodgkin lymphoma (n = 1). EBV was positive in 35 cases (73%). A detailed examination of the TME with image analysis-based quantification in 22 cases revealed an inflammatory TME despite underlying immunosuppression and significant differences in its density and composition depending on type of transplant, PTLD subtypes, and EBV status. Tumor-associated macrophages (TAMs) expressing CD163 (p = 0.0022) and Mannose (p = 0.0016) were enriched in PTLD after HCT. Double stains also showed differences in macrophage polarization, with more frequent M1 polarization after HCT (p = 0.0321). Higher counts for TAMs (CD163 (p = 0.0008) and cMaf (p = 0.0035)) as well as in the T cell compartment (Granzyme B (p = 0.0028), CD8 (p = 0.01), and for PD-L1 (p = 0.0305)) were observed depending on EBV status. In conclusion, despite the presence of immunosuppression, PTLD predominantly contains an inflammatory TME characterized by mostly M1-polarized macrophages and cytotoxic T cells. Status post HCT, EBV positivity, and polymorphic subtype are associated with an actively inflamed TME, indicating a specific response of the immune system. Further studies need to elucidate prognostic significance and potential therapeutic implications of the TME in PTLD.
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http://dx.doi.org/10.1007/s00428-020-02985-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203555PMC
June 2021

Mastocytosis.

Am J Clin Pathol 2021 02;155(2):239-266

Department of Pathology, University of Utah School of Medicine, Salt Lake City.

Objectives: The 2019 Workshop of the Society for Hematopathology/European Association for Haematopathology received and reviewed cases covering the spectrum of mastocytosis and related diseases, including morphologic mimics, focusing on recent updates and relevant findings for pathologists.

Methods: The workshop panel reviewed 99 cases of cutaneous and systemic mastocytosis (SM) and SM and associated hematologic neoplasms (SM-AHN).

Results: Despite a common theme of KIT mutation (particularly D816V), mastocytosis is a heterogeneous neoplasm with a wide variety of presentations. This spectrum, including rare subtypes and extramedullary organ involvement, is discussed and illustrated by representative cases.

Conclusions: In the age of targeted treatment aimed at KIT, the accurate diagnosis and classification of mastocytosis has major implications for therapy and further interventions. Understanding the clinical, pathologic, and genetic findings of mastocytosis is crucial for selecting the proper tests to perform and subsequent arrival at a correct diagnosis in this rare disease.
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http://dx.doi.org/10.1093/ajcp/aqaa183DOI Listing
February 2021

Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease.

Blood Adv 2020 11;4(22):5652-5665

Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen-Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany.

Fifty-five cases of t(14;18)- follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)- FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)- FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)- FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P < .05). STAT6 mutations showed a positive correlation with CD23 expression (P < .001). In summary, t(14;18)- FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.
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http://dx.doi.org/10.1182/bloodadvances.2020002944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686888PMC
November 2020

The inflammation in cutaneous lichen planus is dominated by IFN-ϒ and IL-21-A basis for therapeutic JAK1 inhibition.

Exp Dermatol 2021 Feb 12;30(2):262-270. Epub 2020 Nov 12.

Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Cutaneous lichen planus (CLP) and psoriasis (PSO) are both common chronic inflammatory skin diseases for which development of new treatments requires the identification of key targets. While PSO is a typical Th17/IL-17-disorder, there is some evidence that Th1/IFN-ɣ dominate the inflammatory process in CLP. Nonetheless, the immunopathogenesis of CLP is not fully explained and key immunological factors still have to be recognized. In this study, we compared the immune signature of CLP lesions with the well-characterized inflammation present in PSO skin. First, we analysed the histological and immunohistological characteristics of CLP and PSO. Second, we assessed the cytokine expression (IL1A, IL1B, IL4, IL6, IL8, IL10, IL17A, IL19, IL21, IL22, IL23A, IL13, IFNG, TNF, IL12A, IL12B and IL36G) of lesional skin of CLP with PSO by qPCR. Histology revealed a similar epidermal thickness in CLP and PSO. Immunohistochemically, both diseases presented with an inflammatory infiltrate mainly composed by CD3 CD4 T cells rather than CD3 CD8 . Importantly, mRNA analysis showed a distinct cytokine signature: while levels of IL12B, IL1A, IL6 and IL23 were similar between the two groups, the characteristic PSO-associated cytokines IL8, IL17A, IL22, IL19 and IL36G were expressed at very low levels in CLP. In contrast, CLP lesional skin was dominated by the expression of IFNG, IL21, IL4, IL12A and TNF. Immunohistochemistry confirmed the dominance of IL-21, IFN-ɣ and also pSTAT1 in the dermal infiltrate of CLP, while IL-17A was more present in PSO. Collectively, this study improves our understanding of the immunological factors dominating CLP. The dominating cytokines and signalling proteins identified suggest that anti-cytokine therapeutics like JAK inhibitors may be beneficial in CLP.
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http://dx.doi.org/10.1111/exd.14226DOI Listing
February 2021

Genetic Loss of LCK Kinase Leads to Acceleration of Chronic Lymphocytic Leukemia.

Front Immunol 2020 2;11:1995. Epub 2020 Sep 2.

Department of Hematology, Oncology and Clinical Immunology and Rheumatology, University of Tübingen, Tübingen, Germany.

Most patients with chronic lymphocytic leukemia (CLL) exhibit an indolent disease course and unresponsive B cell receptors (BCRs) exemplified by an anergic phenotype of their leukemic cells. In up to 5% of patients, CLL transforms from an indolent subtype to an aggressive form of B cell lymphoma (Richter's syndrome), which is associated with worse disease outcome and severe downregulation of NFAT2. Here we show that ablation of the tyrosine kinase LCK, which has previously been characterized as a main NFAT2 target gene in CLL, leads to loss of the anergic phenotype, thereby restoring BCR signaling, which results in an acceleration of CLL. Our study identifies LCK as a main player in mediating BCR unresponsiveness and its role as a crucial regulator of anergy in CLL.
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http://dx.doi.org/10.3389/fimmu.2020.01995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492521PMC
April 2021

C-Cbl regulates c-MPL receptor trafficking and its internalization.

J Cell Mol Med 2020 11 20;24(21):12491-12503. Epub 2020 Sep 20.

Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany.

Thrombocyte formation from megakaryocyte and their progenitor cells is tightly regulated by thrombopoietin (TPO) and its receptor c-MPL, thereby maintaining physiological functionality and numbers of circulating platelets. In patients, dysfunction of this regulation could cause thrombocytopenia or myeloproliferative syndromes. Since regulation of this pathway is still not completely understood, we investigated the role of the ubiquitin ligase c-Cbl which was previously shown to negatively regulated c-MPL signalling. We developed a new conditional mouse model using c-Cbl Pf4 mice and demonstrated that platelet-specific knockout of c-Cbl led to severe microthrombocytosis and impaired uptake of TPO and c-MPL receptor internalization. Furthermore, we characterized a constitutive STAT5 activation c-Cbl KO platelets. This study identified c-Cbl as a potential player in causing megakaryocytic and thrombocytic disorders.
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http://dx.doi.org/10.1111/jcmm.15785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687000PMC
November 2020

Genetic evolution of in situ follicular neoplasia to aggressive B-cell lymphoma of germinal center subtype.

Haematologica 2020 08 27. Epub 2020 Aug 27.

Institute of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tuebingen, Tuebingen, Germany;

In situ follicular neoplasia (ISFN) is the earliest morphologically identifiable precursor of follicular lymphoma (FL). Although it is genetically less complex than FL and has low risk for progression, ISFN already harbors secondary genetic alterations, in addition to the defining t(14;18)(q32;q21) translocation. FL, in turn, frequently progresses to diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). By BCL2 staining of available reactive lymphoid tissue obtained at any time point in patients with aggressive B-cell lymphoma (BCL), we identified 10 paired cases of ISFN and DLBCL/HGBL, including 6 de novo tumors and 4 transformed from FL as intermediate step, and investigated their clonal evolution using microdissection and next generation sequencing. A clonal relationship between ISFN and aggressive BCL was established by immunoglobulin and/or BCL2 rearrangements and/or the demonstration of shared somatic mutations for all 10 cases. Targeted sequencing revealed CREBBP, KMT2D, EZH2, TNFRSF14 and BCL2 as the genes most frequently mutated already in ISFN. Based on the distribution of private and shared mutations, two patterns of clonal evolution were evident. In most cases, the aggressive lymphoma, ISFN and, when present, FL revealed divergent evolution from a common progenitor, whereas linear evolution with sequential accumulation of mutations was less frequent. In conclusion, we demonstrate for the first time that t(14;18)+ aggressive BCL can arise from ISFN without clinically evident FL as intermediate step and that during this progression, branched evolution is common.
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http://dx.doi.org/10.3324/haematol.2020.254854DOI Listing
August 2020

Immune landscape in Burkitt lymphoma reveals M2-macrophage polarization and correlation between PD-L1 expression and non-canonical EBV latency program.

Infect Agent Cancer 2020 6;15:28. Epub 2020 May 6.

11Department of Cellular Pathology, University College Hospital, London, London UK.

Background: The Tumor Microenviroment (TME) is a complex milieu that is increasingly recognized as a key factor in multiple stages of disease progression and responses to therapy as well as escape from immune surveillance. However, the precise contribution of specific immune effector and immune suppressor components of the TME in Burkitt lymphoma (BL) remains poorly understood.

Methods: In this paper, we applied the computational algorithm CIBERSORT to Gene Expression Profiling (GEP) datasets of 40 BL samples to draw a map of immune and stromal components of TME. Furthermore, by multiple immunohistochemistry (IHC) and multispectral immunofluorescence (IF), we investigated the TME of additional series of 40 BL cases to evaluate the role of the Programmed Death-1 and Programmed Death Ligand-1 (PD-1/PD-L1) immune checkpoint axis.

Results: Our results indicate that M2 polarized macrophages are the most prominent TME component in BL. In addition, we investigated the correlation between PD-L1 and latent membrane protein-2A (LMP2A) expression on tumour cells, highlighting a subgroup of BL cases characterized by a non-canonical latency program of EBV with an activated PD-L1 pathway.

Conclusion: In conclusion, our study analysed the TME in BL and identified a tolerogenic immune signature highlighting new potential therapeutic targets.
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http://dx.doi.org/10.1186/s13027-020-00292-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201729PMC
May 2020

Existence of reprogrammed lymphoma stem cells in a murine ALCL-like model.

Leukemia 2020 12 17;34(12):3242-3255. Epub 2020 Mar 17.

Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany.

While cancer stem cells are well established in certain hematologic and solid malignancies, their existence in T cell lymphoma is unclear and the origin of disease is not fully understood. To examine the existence of lymphoma stem cells, we utilized a mouse model of anaplastic large cell lymphoma. Established NPM-ALK lymphomas contained heterogeneous cell populations ranging from mature T cells to undifferentiated hematopoietic stem cells. Interestingly, CD4/CD8 double negative (DN) lymphoma cells aberrantly expressed the T cell receptor α/β chain. Serial transplantation of sorted CD4/CD8 and DN lymphoma subpopulations identified lymphoma stem cells within the DN3/DN4 T cell population, whereas all other subpopulations failed to establish serial lymphomas. Moreover, transplanted lymphoma DN3/DN4 T cells were able to differentiate and gave rise to mature lymphoma T cells. Gene expression analyses unmasked stem-cell-like transcriptional regulation of the identified lymphoma stem cell population. Furthermore, these lymphoma stem cells are characterized by low CD30 expression levels, which might contribute to limited long-term therapeutic success in patients treated with anti-CD30-targeted therapies. In summary, our results highlight the existence of a lymphoma stem cell population in a NPM-ALK-driven CD30 mouse model, thereby giving the opportunity to test innovative treatment strategies developed to eradicate the origin of disease.
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http://dx.doi.org/10.1038/s41375-020-0789-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685983PMC
December 2020

Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours.

Nat Commun 2020 03 12;11(1):1335. Epub 2020 Mar 12.

German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.

Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16/p19 (Cdkn2a) or p21 (Cdkn1a) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication.
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http://dx.doi.org/10.1038/s41467-020-14987-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067802PMC
March 2020

GD2-targeted chimeric antigen receptor T cells prevent metastasis formation by elimination of breast cancer stem-like cells.

Oncoimmunology 2020 7;9(1):1683345. Epub 2019 Nov 7.

Department of Pediatric Hematology and Oncology, University Children's Hospital Tuebingen, Tuebingen, Germany.

Expression of the disialoganglioside GD2 has been identified as a marker antigen associated with a breast cancer stem-like cell (BCSC) phenotype. Here, we report on the evaluation of GD2 as a BCSC-specific target antigen for immunotherapy. GD2 expression was confirmed at variable degree in a set of breast cancer cell lines, predominantly in triple-negative breast cancer (TNBC). To target GD2, we have generated novel anti-GD2 chimeric antigen receptors (GD2-CAR), based on single-chain variable fragments (scFv) derived from the monoclonal antibody (mAb) ch14.18, also known as dinutuximab beta. Expressed on T cells, GD2-CARs mediated specific GD2-dependent T-cell activation and target cell lysis. In contrast to previously described GD2-CARs, no signs of exhaustion by tonic signaling were found. Importantly, application of GD2-CAR expressing T cells (GD2-CAR-T) in an orthotopic xenograft model of TNBC (MDA-MB-231) halted local tumor progression and completely prevented lung metastasis formation. In line with the BCSC model, GD2 expression was only found in a subpopulation (4-6%) of MDA-MB-231 cells before injection. Significant expansion of GD2-CAR-T in tumor-bearing mice as well as T-cell infiltrates in the primary tumor and the lungs were found, indicating site-specific activation of GD2-CAR-T. Our data strongly support previous findings of GD2 as a BCSC-associated antigen. GD2-targeted immunotherapies have been extensively studied in human. In conclusion, GD2-CAR-T should be considered a promising novel approach for GD2-positive breast cancer, especially to eliminate disseminated tumor cells and prevent metastasis formation.
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http://dx.doi.org/10.1080/2162402X.2019.1683345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959445PMC
July 2021

shRNA-mediated inhibition of PhosphoGlycerate Kinase 1 (PGK1) enhances cytotoxicity of intraperitoneal chemotherapy in peritoneal metastasis of gastric origin.

Eur J Surg Oncol 2020 04 15;46(4 Pt A):613-619. Epub 2020 Jan 15.

Institute of Pathology, University of Tübingen, Tübingen, Germany.

Background: Phosphoglycerate kinase 1 (PGK1) plays metabolic, kinase and translational roles in Peritoneal metastasis (PM) of gastric origin and is associated with chemoresistance. Silencing PGK1 might potentiate the effect of chemotherapy.

Methods: In an orthoptic xenograft nude mice model, human gastric cancer cells (MKN45) were grown in 22 donor animals. Solid tumors were then grafted into the gastric subserosa of 102 recipient animals and allowed to grow for 10 days. Animals were randomized into 7 groups: Five test groups: 1) Mitomycin C (MMC), 2) MMC and small hairpin RNA silencing of PGK1 with an adenoviral vector (Adv-shPGK1), 3) 5-fluorouracil (5-FU), 4) 5-FU and Adv-shPGK1, 5) Adv-shPGK1 alone; two control groups: 1) Sham (NaCl 0.9%), 2) empty viral vector. Intraperitoneal therapy was administered on postoperative day (POD) 11 and 18. Animals were sacrificed at POD 21, analysis was blinded to therapy.

Results: Adding Adv-shPGK1 to 5-FU reduced the number (0.23 ± 0.43 vs. 1.36 ± 1.00, p = 0.005) and weight (0,005 ± 0.012 mg vs. 0.05 ± 0.08 mg, p = 0.002) of PM as compared to 5-FU alone. The effect of adding Adv-shPGK1 to MMC did not reach statistical significance. Mortality was not increased by adding Adv-shPGK1 to chemotherapy but was increased by Adv-shPGK1 alone as compared to sham.

Conclusion: In this experimental model, combined therapy with chemotherapy and Adv-shPGK1 improves control of PM of gastric origin as compared to chemotherapy alone and might counteract chemoresistance of PM. A systemic toxicity of Adv-shPGK1 cannot be excluded.
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http://dx.doi.org/10.1016/j.ejso.2020.01.018DOI Listing
April 2020

Cancer immunotherapy is accompanied by distinct metabolic patterns in primary and secondary lymphoid organs observed by non-invasive F-FDG-PET.

Theranostics 2020 1;10(2):925-937. Epub 2020 Jan 1.

Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, 72076 Tübingen, Germany.

Cancer immunotherapy depends on a systemic immune response, but the basic underlying mechanisms are still largely unknown. Despite the very successful and widespread use of checkpoint inhibitors in the clinic, the majority of cancer patients do not benefit from this type of treatment. In this translational study, we investigated whether noninvasive positron emission tomography (PET) imaging using 2-[F]fluoro-2-deoxy-D-glucose (F-FDG) is capable of detecting immunotherapy-associated metabolic changes in the primary and secondary lymphoid organs and whether this detection enables the prediction of a successful anti-cancer immune response. RIP1-Tag2 mice with progressed endogenous insular cell carcinomas underwent a combined cancer immunotherapy consisting of CD4 T cells plus monoclonal antibodies (mAbs) against programmed death ligand-1 (PD-L1) and lymphocyte activation gene-3 (LAG-3) or a sham treatment after radiation-mediated immune cell depletion. A second cohort of RIP1-Tag2 mice underwent exclusive checkpoint inhibitor therapy (CIT) using anti-PD-L1/LAG-3 mAbs or sham treatment without initial immune cell depletion to mimic the clinical situation. All mice were monitored by F-FDG-PET combined with anatomical magnetic resonance imaging (MRI). In addition, we retrospectively analyzed PET / computed tomography (CT) scans (PET/CT) regarding F-FDG uptake of CIT-treated metastatic melanoma patients in the spleen (n=23) and bone marrow (BM; n=20) as well as blood parameters (n=17-21). RIP1-Tag2 mice with advanced insular cell carcinomas treated with combination immunotherapy exhibited significantly increased F-FDG uptake in the spleen compared to sham-treated mice. Histopathology of the spleens from treated mice revealed atrophy of the white pulp with fewer germinal centers and an expanded red pulp with hyperplasia of neutrophils than those of sham-treated mice. Immunohistochemistry and flow cytometry analyses of the spleens revealed a lower number of T cells and a higher number of neutrophils compared to those in the spleens of sham-treated mice. Flow cytometry of the BM showed enhanced activation of T cells following the treatment schemes that included checkpoint inhibitors. The ratio of F-FDG uptake at baseline to the uptake at follow-up in the spleens of exclusively CIT-treated RIP1-Tag2 mice was significantly enhanced, but the ratio was not enhanced in the spleens of the sham-treated littermates. Flow cytometry analysis confirmed a reduced number of T cells in the spleens of exclusively CIT-treated mice compared to that of sham-treated mice. A retrospective analysis of clinical F-FDG-PET/CT scans revealed enhanced F-FDG uptake in the spleens of some successfully CIT-treated patients with metastatic melanoma, but there were no significant differences between responders and non-responders. The analysis of the BM in clinical F-FDG-PET/CT scans with a computational segmentation tool revealed significantly higher baseline F-FDG uptake in patients who responded to CIT than in non-responders, and this relationship was independent of bone metastasis, even in the baseline scan. Thus, we are presenting the first translational study of solid tumors focusing on the metabolic patterns of primary and secondary lymphoid organs induced by the systemic immune response after CIT. We demonstrate that the widely available F-FDG-PET modality is an applicable translational tool that has high potential to stratify patients at an early time point.
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http://dx.doi.org/10.7150/thno.35989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929998PMC
April 2021

Epstein - Barr virus positive T and NK-cell lymphoproliferations: Morphological features and differential diagnosis.

Semin Diagn Pathol 2020 Jan 17;37(1):32-46. Epub 2019 Dec 17.

Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany. Electronic address:

The spectrum of Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations is broad and ranges from reactive self-limited disorders to neoplastic processes with a fulminant clinical course. EBV plays an important role promoting lymphomagenesis, although the precise mechanisms remain elusive. EBV-positive lymphoproliferative disorders (LPD) are more common in East Asia (China, Japan, Korea and Taiwan), and Latin America suggesting a strong genetic predisposition. The revised 2016 World Health Organization (WHO) lymphoma classification recognizes the following malignant NK- and T-cell lymphomas; extranodal NK/T-cell lymphoma, nasal type (ENKTCL), aggressive NK-cell leukemia (ANKL), and the provisional entity within the group of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) "primary EBV-positive nodal T or NK cell lymphoma". Disorders presenting mainly in children and young adults include chronic active EBV infection (CAEBV) - systemic and cutaneous forms - which are not considered malignant disorders but were included in the WHO classification for the first time because of the differential diagnosis with other T- or NK-cell lymphomas. CAEBV, cutaneous form, includes hydroa vacciniforme-like LPD (HV-LPD) and severe mosquito bite allergy (SMBA). Finally, systemic EBV-positive T-cell lymphoma of childhood was recognized as lymphoma because of its fulminant clinical course. Given the shared pathogenesis of these disorders, overlapping features are common demanding a close clinical, morphological and molecular correlation for an accurate diagnosis. This review summarizes the clinical, histopathological and molecular features of EBV-associated T and NK-cell LPD, highlighting the main features that might aid in the differential diagnosis.
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http://dx.doi.org/10.1053/j.semdp.2019.12.004DOI Listing
January 2020

Epstein-Barr virus NK and T cell lymphoproliferative disease: report of a 2018 international meeting.

Leuk Lymphoma 2020 04 13;61(4):808-819. Epub 2019 Dec 13.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Epstein-Barr virus (EBV) normally infects B cells, but in some persons the virus infects T or NK cells. Infection of B cells can result in infectious mononucleosis, and the virus is associated with several B cell malignancies including Hodgkin lymphoma, Burkitt lymphoma, and diffuse large B cell lymphoma. Infection of T or NK cells with EBV is associated with extranodal NK/T cell lymphoma, aggressive NK-cell leukemia, systemic EBV-associated T-cell lymphoma, and chronic active EBV disease, which in some cases can include hydroa vacciniforme-like lymphoproliferative disease and severe mosquito bite allergy. While NK and T cell lymphoproliferative disease is more common in Asia and Latin America, increasing numbers of cases are being reported from the United States and Europe. This review focuses on classification, clinical findings, pathogenesis, and recent genetic advances in NK and T cell lymphoproliferative diseases associated with EBV.
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http://dx.doi.org/10.1080/10428194.2019.1699080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189159PMC
April 2020

Mutational profile and EBV strains of extranodal NK/T-cell lymphoma, nasal type in Latin America.

Mod Pathol 2020 05 10;33(5):781-791. Epub 2019 Dec 10.

Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany.

Extranodal NK/T-cell lymphoma (ENKTL) is an Epstein-Barr virus (EBV) associated lymphoma, prevalent in Asia and Latin America. Studies in Asian cohorts have identified some recurrent gene mutations in ENKTL; however, the mutational landscape of ENKTL in Latin America is unknown. In this study, we investigated the mutational profile and EBV strains of 71 ENKTL cases from Latin America (42 from Mexico, 17 from Peru, and 12 from Argentina) and compared it with Asian cohorts. The mutational analysis was performed by next generation sequencing (NGS) using an Ion AmpliSeq™ custom panel covering for the most frequently mutated genes identified in ENKTL. STAT3 was the most frequent mutated gene (16 cases: 23%), followed by MSN (10 cases; 14%), BCOR (9 cases; 13%), DDX3X (6 cases; 8%), TP53 (6 cases; 8%), MGA (3 cases; 4%), JAK3 (2 cases; 3%), and STAT5B (1 case; 1%). Mutations in STAT3, BCOR, and DDX3X were nearly mutually exclusive, suggesting different molecular pathways involved in the pathogenesis of ENKTL; whereas mutations in MGA, MSN, and TP53 were concomitant with other mutations. Most cases (75%) carried Type A EBV without the 30-bp LMP1 gene deletion. The overall survival was significantly associated with serum LDH level, Eastern Cooperative Oncology Group (ECOG) performance status, International Prognostic Index (IPI) score, and therapy (p < 0.05), but not associated with any mutation, EBV strain or deletion in EBV LMP1 gene. In conclusion, mutational analysis of ENKTL from Latin America reveals frequent gene mutations leading to activation of the JAK-STAT pathway (25%), mostly STAT3. Compared to Asian cohorts, BCOR, DDX3X  and TP53 mutations were also identified but with different frequencies. None of these mutations were associated with prognosis.
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http://dx.doi.org/10.1038/s41379-019-0415-5DOI Listing
May 2020

The ParaHox gene Cdx4 induces acute erythroid leukemia in mice.

Blood Adv 2019 11;3(22):3729-3739

Institute of Experimental Cancer Research, Comprehensive Cancer Center and University Hospital of Ulm, Ulm, Germany.

Acute erythroid leukemia (AEL) is a rare and aggressive form of acute leukemia, the biology of which remains poorly understood. Here we demonstrate that the ParaHox gene CDX4 is expressed in patients with acute erythroid leukemia, and that aberrant expression of Cdx4 induced homogenously a transplantable acute erythroid leukemia in mice. Gene expression analyses demonstrated upregulation of genes involved in stemness and leukemogenesis, with parallel downregulation of target genes of Gata1 and Gata2 responsible for erythroid differentiation. Cdx4 induced a proteomic profile that overlapped with a cluster of proteins previously defined to represent the most primitive human erythroid progenitors. Whole-exome sequencing of diseased mice identified recurrent mutations significantly enriched for transcription factors involved in erythroid lineage specification, as well as TP53 target genes partly identical to the ones reported in patients with AEL. In summary, our data indicate that Cdx4 is able to induce stemness and inhibit terminal erythroid differentiation, leading to the development of AEL in association with co-occurring mutations.
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http://dx.doi.org/10.1182/bloodadvances.2019000761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880902PMC
November 2019
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