scholarly journals Mutations in JAK/STAT and NOTCH1 Genes Are Enriched in Post-Transplant Lymphoproliferative Disorders

2022 ◽  
Vol 11 ◽  
Author(s):  
Alexandra Butzmann ◽  
Kaushik Sridhar ◽  
Diwash Jangam ◽  
Hanbing Song ◽  
Amol Singh ◽  
...  
Keyword(s):  
Solid Organ Transplantation ◽  
Major Axis ◽  
Genetic Mutation ◽  
Lymphoproliferative Disorders ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Regulatory Pathways ◽  
Follicular Hyperplasia ◽  
Post Transplant ◽  
Recurrent Mutations

Post-transplant lymphoproliferative disorders (PTLD) are diseases occurring in immunocompromised patients after hematopoietic stem cell transplantation (HCT) or solid organ transplantation (SOT). Although PTLD occurs rarely, it may be associated with poor outcomes. In most cases, PTLD is driven by Epstein-Barr virus (EBV) infection. Few studies have investigated the mutational landscape and gene expression profile of PTLD. In our study, we performed targeted deep sequencing and RNA-sequencing (RNA-Seq) on 16 cases of florid follicular hyperplasia (FFH) type PTLD and 15 cases of other PTLD types that include: ten monomorphic (M-PTLD), three polymorphic (P-PTLD), and two classic Hodgkin lymphoma type PTLDs (CHL-PTLD). Our study identified recurrent mutations in JAK3 in five of 15 PTLD cases and one of 16 FFH-PTLD cases, as well as 16 other genes that were mutated in M-PTLD, P-PTLD, CHL-PTLD and FFH-PTLD. Digital image analysis demonstrated significant differences in single cell area, major axis, and diameter when comparing cases of M-PTLD and P-PTLD to FFH-PTLD. No morphometric relationship was identified with regards to a specific genetic mutation. Our findings suggest that immune regulatory pathways play an essential role in PTLD, with the JAK/STAT pathway affected in many PTLDs.

scholarly journals Recurrent JAK3 Mutations in Post-Transplant Lymphoproliferative Disorder

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5226-5226
Author(s):  
Alexandra Butzmann ◽  
Diwash Jangam ◽  
Jyoti Kumar ◽  
Kaushik Sridhar ◽  
Benjamin A Pinsky ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Lymphoid Tissues ◽  
Hematopoietic Stem ◽  
Regulatory Pathways ◽  
Follicular Hyperplasia ◽  
Post Transplant ◽  
Transplant Patients ◽  
Recurrent Mutations

Post-transplant lymphoproliferative disorders (PTLD) are diverse in morphology, immunophenotype and clinical outcomes, occurring in immune compromised patients after hematopoietic stem cell transplantation (HCT) or single organ transplantation (SOT). Predicting the outcome of PTLDs is complex. In most of cases PTLD is driven by Epstein-Barr virus (EBV) infection, though the etiology of EBV negative cases is unknown. There have been only few studies investigating the mutational landscape and gene expression of PTLD. In our study we performed targeted DNA deep sequencing and RNA expression profiling (RNA-Seq) on the hematopoietic lymphoid tissues of 15 post-transplant patients with PTLD and 16 post-transplant patients with follicular hyperplasia (FH) after HCT or SOT. Recurrent mutations in JAK3 were identified in five of 16 PTLD cases and one of 16 follicular hyperplasia cases. We additionally identified mutations in the PIK3CD gene in four PTLD cases and NOTCH1 mutations in 2 PTLD and four FH cases. 17 other genes were commonly mutated in both groups. Gene expression profiles differed between both groups. Genes involved in regulating the immune system were unregulated in PTLD. We also saw a stronger expression of T-cells and a weaker expression of B-cells within the PTLD group when compared with FH. Our findings suggest an important role for immune regulatory pathways in the pathogenesis of PTLD, with the JAK/STAT pathway being a central recurrent key metabolic pathway. Figure Disclosures Ohgami: Agilent technologies: Other: received support/funding.

scholarly journals Posttransplant Lymphoproliferative Disorders in Neuronal Xenotransplanted Macaques

2016 ◽  
Vol 54 (2) ◽  
pp. 336-344 ◽  
Author(s):  
L. Cavicchioli ◽  
S. Ferraresso ◽  
S. Westmoreland ◽  
S. Kaliyaperumal ◽  
H. Knight ◽  
...  
Keyword(s):  
Cell Function ◽  
Solid Organ Transplantation ◽  
Lymphoproliferative Disorders ◽  
World Health ◽  
Nuclear Antigen ◽  
Solid Organ ◽  
Double Labeling ◽  
Hematopoietic Stem ◽  
Health Organization ◽  
Posttransplant Lymphoproliferative Disorders

Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations that occur in the setting of depressed T-cell function due to immunosuppressive therapy used following solid organ transplantation, hematopoietic stem cell transplantation, and also xenotransplantation. In the present study, 28 immunosuppressed parkinsonian Macaca fascicularis were intracerebrally injected with wild-type or CTLA4-Ig transgenic porcine xenografts to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Nine of 28 (32%) immunosuppressed primates developed masses compatible with PTLD, located mainly in the gastrointestinal tract and/or nasal cavity. The masses were classified as monomorphic PTLD according to the World Health Organization classification. Immunohistochemistry and polymerase chain reaction (PCR) analyses revealed that the PTLDs were associated with macaca lymphocryptovirus as confirmed by double-labeling immunohistochemistry for CD20 and Epstein-Barr nuclear antigen 2 (EBNA-2), where the viral protein was located within the CD20+ neoplastic B cells. In sera from 3 distinct phases of the experimental life of the primates, testing by quantitative PCR revealed a progression of the viral load that paralleled the PTLD progression and no evidence of zoonotic transmission of porcine lymphotropic herpesvirus through xenoneuronal grafts. These data suggest that monitoring the variation of macaca lymphocryptovirus DNA in primates could be used as a possible early diagnostic tool for PTLD progression, allowing preemptive treatment such as immunosuppression therapy reduction.

scholarly journals Post-transplant Lymphoproliferative Disorders: Single Center Case Series and Literature Review

2020 ◽  
pp. 1-6
Author(s):  
Sumayyah Altamimi ◽  
◽  
Mohamed Al Shuaibi ◽  
Mohamed Alnahdi ◽  
Abdulrahman Altheaby ◽  
...  
Keyword(s):  
De Novo ◽  
Organ Transplant ◽  
Tumor Development ◽  
Case Series ◽  
Standard Of Care ◽  
Lymphoproliferative Disorders ◽  
Outcome Analysis ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Post Transplant

Post-transplant lymphoproliferative disorders (PTLD) are referred to lymphoid and/or plasmacytic proliferation which occur as result of immunosuppression therapy in patient underwent solid organ or allogeneic hematopoietic stem cell transplantation. Among solid organ transplant recipients, it accounts approximately 20% of all cancers. Epstein-Barr virus (EBV) has been linked to the pathogenesis of PTLD when EBV was identified in the tumor biopsies. In most affected patients, PTLD occurs as a result of proliferation of EBV positive B cell following immunosuppression and impaired Tcell immune activity. EBV negative PTLD has been documented but no clear etiology has been confirmed, however theories of previous exposure to EBV which is completely cleared at the time of PTLD is diagnosed, different viruses or chronic antigenic stimulation all been considered as provoking factors for tumor development. Clinical symptomatology at presentation of patients with PTLD is usually indistinct from de novo lymphoproliferative disorders and chemotherapy protocols in this group of patients are generally similar to the standard of care of lymphoma treatment according to the subtype in addition to cessation or dose reduction of immunosuppressive therapy. We report our experience and outcome analysis in PTLD management among 23 patients from our institution treated between 2011 and 2019.

scholarly journals EBV-Associated Post-Transplant Lymphoproliferative Disease (PTLD) in Allogeneic Transplantation

2021 ◽  
Vol 8 (3) ◽  
Author(s):  
Cutini I ◽  
◽  
Peruzzi B ◽  
Caporale R ◽  
Nozzoli C ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Solid Organ Transplantation ◽  
B Cell Lymphoma ◽  
Allogeneic Transplantation ◽  
Lymphoproliferative Disease ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Control Virus ◽  
Life Threatening

Post-Transplant Lymphoproliferative Disease (PTLD) following both Solid Organ Transplantation (SOT) and Hematopoietic Stem Cell Transplantation (HSCT) is a rare life-threatening complication. The majority of PLTDs are associated to Epstein Bar Virus (EBV) [1] reactivation, usually in the early phase [2] after transplant, when the patient is severely immunocompromised and is unable to control virus replication [3]. Despite the mortality of EBV-associated PTLD has been reduced over the years, the different histological patterns of its presentation, ranging from indolent to high grade B cell lymphoma, still play a role in the outcome. Herein, we report the case of a 60-years-old man diagnosed with acute myeloid leukemia who underwent allogeneic transplantation and developed a fatal Hemophagocytic Histiocytosis (HLH) secondary to an aggressive EBV-associated PTLD, not responding to a rituximab-based treatment.

Risk factors evaluation of post-transplant lymphoproliferative disorders after allogeneic haematopoietic stem cell transplantation with comparison between paediatric and adult

2021 ◽  
pp. jclinpath-2021-207492
Author(s):  
Ding Bao Chen ◽  
Xiao Yang Liu ◽  
Fang Zhou Kong ◽  
Qian Jiang ◽  
Dan Hua Shen
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Cell Lymphoma ◽  
Solid Organ Transplantation ◽  
B Cell Lymphoma ◽  
Donor Lymphocyte Infusion ◽  
Haematopoietic Stem Cell ◽  
Solid Organ ◽  
Follicular Hyperplasia ◽  
Post Transplant

To describe the clincopathological features and evaluate risk factors of post-transplant lymphoproliferative disorder (PTLD) after allogeneic haematopoietic stem cell transplants (allo-HSCT), with comparison between paediatric and adult .Clinicopathological features of 81 cases of PTLD after allo-HSCT were analysed by histopatholgy, immunohistochemistry and in situ hybridisatioin.The cases included 58 males and 23 females with a median age of 26.7 years (range 6–55 years) and the PTLDs developed 1–60 months post-transplant (mean 5.9 months). The histological types indicated 10 cases of non-destructive PTLD, including 4 of plasmacytic hyperplasia, 5 of infectious mononucleosis and 1 of florid follicular hyperplasia. Fifty-six cases were polymorphic PTLD, and 15 were monomorphic PTLD, including thirteen of diffuse large B cell lymphoma, 1 of extranodal nasal type natural killer (NK)/T cell lymphoma and 1 of plasmablastic lymphoma. Foci and sheets of necrosis were observed in 31 cases. The infected ratio of Epstein-Barr virus (EBV) was 91.4%. Some cases were treated by reduction of immunosuppression, antiviral therapy, donor lymphocyte infusion or anti-CD20 monoclonal rituximab. Thirty-three cases died. Compared with that of adult, overall survival of paediatric recipient may be better.The first half year after allo-HSCT is very important for the development of PTLD. Type of PTLD, EBV infection and graft-versus-host disease are risk factors. The prognosis of PTLD is poor, and PTLD after allo-HSCT exhibits some features different from that after solid organ transplantation and some differences existing between adult and paediatric recipients.

scholarly journals Analysis of Post-Transplant Lymphoproliferative Disorder (PTLD) Outcomes with Epstein–Barr Virus (EBV) Assessments—A Single Tertiary Referral Center Experience and Review of Literature

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 899
Author(s):  
Eric Lau ◽  
Justin Tyler Moyers ◽  
Billy Chen Wang ◽  
Il Seok Daniel Jeong ◽  
Joanne Lee ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Tertiary Referral Center ◽  
Post Transplant ◽  
Barr Virus ◽  
Significant Difference ◽  
Epstein Barr

Post-transplant lymphoproliferative disorders (PTLDs) are lymphoid or plasmacytic proliferations ranging from polyclonal reactive proliferations to overt lymphomas that develop as consequence of immunosuppression in recipients of solid organ transplantation (SOT) or allogeneic bone marrow/hematopoietic stem cell transplantation. Immunosuppression and Epstein–Barr virus (EBV) infection are known risk factors for PTLD. Patients with documented histopathologic diagnosis of primary PTLD at our institution between January 2000 and October 2019 were studied. Sixty-six patients with PTLD following SOT were followed for a median of 9.0 years. The overall median time from transplant to PTLD diagnosis was 5.5 years, with infant transplants showing the longest time to diagnosis at 12.0 years, compared to pediatric and adolescent transplants at 4.0 years and adult transplants at 4.5 years. The median overall survival (OS) was 19.0 years. In the monomorphic diffuse large B-cell (M-DLBCL-PTLD) subtype, median OS was 10.7 years, while median OS for polymorphic subtype was not yet reached. There was no significant difference in OS in patients with M-DLBCL-PTLD stratified by quantitative EBV viral load over and under 100,000 copies/mL at time of diagnosis, although there was a trend towards worse prognosis in those with higher copies.

scholarly journals Natural Killer Cells in Post-Transplant Lymphoproliferative Disorders

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1836
Author(s):  
Cecilia Nakid-Cordero ◽  
Marine Baron ◽  
Amélie Guihot ◽  
Vincent Vieillard
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Critical Role ◽  
Early Response ◽  
Lymphoproliferative Disorders ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Post Transplant

Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening complications arising after solid organ or hematopoietic stem cell transplantations. Although the majority of these lymphoproliferations are of B cell origin, and are frequently associated with primary Epstein–Barr virus (EBV) infection or reactivation in the post-transplant period, rare cases of T cell and natural killer (NK) cell-originated PTLDs have also been described. A general assumption is that PTLDs result from the impairment of anti-viral and anti-tumoral immunosurveillance due to the long-term use of immunosuppressants in transplant recipients. T cell impairment is known to play a critical role in the immune-pathogenesis of post-transplant EBV-linked complications, while the role of NK cells has been less investigated, and is probably different between EBV-positive and EBV-negative PTLDs. As a part of the innate immune response, NK cells are critical for protecting hosts during the early response to virus-induced tumors. The complexity of their function is modulated by a myriad of activating and inhibitory receptors expressed on cell surfaces. This review outlines our current understanding of NK cells in the pathogenesis of PTLD, and discusses their potential implications for current PTLD therapies and novel NK cell-based therapies for the containment of these disorders.

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

2020 ◽  
Author(s):  
Mathis Overkamp ◽  
Massimo Granai ◽  
Irina Bonzheim ◽  
Julia Steinhilber ◽  
Jens Schittenhelm ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tumor Microenvironment ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Lymphoproliferative Disorders ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Post Transplant

AbstractPost-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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