scholarly journals Targeting phosphatidylinositol 3 kinase-β and -δ for Bruton tyrosine kinase resistance in diffuse large B-cell lymphoma

2020 ◽  
Vol 4 (18) ◽  
pp. 4382-4392
Author(s):  
Neeraj Jain ◽  
Satishkumar Singh ◽  
Georgios Laliotis ◽  
Amber Hart ◽  
Elizabeth Muhowski ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Phosphatidylinositol 3 Kinase ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Bruton Tyrosine Kinase ◽  
Large B Cell ◽  
Resistant Cells

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma; 40% of patients relapse after a complete response or are refractory to therapy. To survive, the activated B-cell (ABC) subtype of DLBCL relies upon B-cell receptor signaling, which can be modulated by the activity of Bruton tyrosine kinase (BTK). Targeting BTK with ibrutinib, an inhibitor, provides a therapeutic approach for this subtype of DLBCL. However, non-Hodgkin lymphoma is often resistant to ibrutinib or acquires resistance soon after exposure. We explored how this resistance develops. We generated 3 isogenic ibrutinib-resistant DLBCL cell lines and investigated the deregulated pathways known to be associated with tumorigenic properties. Reduced levels of BTK and enhanced phosphatidylinositol 3-kinase (PI3K)/AKT signaling were hallmarks of these ibrutinib-resistant cells. Upregulation of PI3K-β expression was demonstrated to drive resistance in ibrutinib-resistant cells, and resistance was reversed by the blocking activity of PI3K-β/δ. Treatment with the selective PI3K-β/δ dual inhibitor KA2237 reduced both tumorigenic properties and survival-based PI3K/AKT/mTOR signaling of these ibrutinib-resistant cells. In addition, combining KA2237 with currently available chemotherapeutic agents synergistically inhibited metabolic growth. This study elucidates the compensatory upregulated PI3K/AKT axis that emerges in ibrutinib-resistant cells.

scholarly journals Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma

2019 ◽  
Author(s):  
Neeraj Jain ◽  
Ondrej Havranek ◽  
Ram Kumar Singh ◽  
Tamer Khashab ◽  
Fazal Shirazi ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Phosphatidylinositol 3 Kinase ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Ibrutinib Resistance ◽  
Large B Cell ◽  
Phosphatidylinositol 3 ◽  
Resistant Cells

AbstractDiffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma; 40% of patients relapse following a complete response or are refractory to therapy. The activated subtype of diffuse large B-cell lymphoma relies upon B-cell receptor signaling for survival; this signaling can be modulated by the activity of Bruton’s tyrosine kinase. Targeting that kinase with its inhibitor ibrutinib provides a potential therapeutic approach for the activated B-cell subtype of diffuse large B-cell lymphoma. However, non-Hodgkin lymphoma is often resistant to ibrutinib or soon develops resistance after exposure to it. In this study, we explored the development of acquired ibrutinib resistance. After generating three isogenic ibrutinib-resistant diffuse large B-cell lymphoma cell lines, we investigated the deregulated pathways that are associated with colony formation, growth rates, and tumorigenic properties. We found that reduced levels of Bruton’s tyrosine kinase and enhanced phosphatidylinositol 3-kinase/AKT signaling were hallmarks of these ibrutinib-resistant cells. Upregulation of phosphatidylinositol-3-kinase-beta expression in those cells drove resistance and was reversed by the blocking activity of phosphatidylinositol-3-kinase-beta/delta. Treatment with the selective phosphatidylinositol-3-kinase-beta/delta dual inhibitor KA2237 reduced both tumorigenic properties and survival-based phosphatidylinositol-3-kinase/AKT/mTOR signaling of these ibrutinib-resistant cells. Additionally, combining KA2237 with currently available chemotherapeutic agents synergistically inhibited the metabolic growth of these ibrutinib-resistant cells. This study elucidates the compensatory upregulated phosphatidylinositol-3-kinase/AKT axis that emerges in ibrutinib-resistant cells.

Metody cytogenetyki molekularnej w różnicowaniu agresywnych B-NHL

2019 ◽  
Vol 50 (3) ◽  
pp. 109-115
Author(s):  
Beata Grygalewicz
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
World Health ◽  
High Grade ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Health Organization ◽  
Large B Cell

StreszczenieB-komórkowe agresywne chłoniaki nieziarnicze (B-cell non-Hodgkin lymphoma – B-NHL) to heterogenna grupa nowotworów układu chłonnego, wywodząca się z obwodowych limfocytów B. Aberracje cytogenetyczne towarzyszące B-NHL to najczęściej translokacje onkogenów takich jak MYC, BCL2, BCL6 w okolice genowych loci dla łańcuchów ciężkich lub lekkich immunoglobulin. W niektórych przypadkach dochodzi do wystąpienia kilku wymienionych aberracji jednocześnie, tak jak w przypadkach przebiegających z równoczesną translokacją genów MYC i BCL2 (double hit), niekiedy także z obecnością rearanżacji BCL6 (triple hit). Takie chłoniaki cechuje szczególnie agresywny przebieg kliniczny. Obecnie molekularna diagnostyka cytogenetyczna przy użyciu techniki fluorescencyjnej hybrydyzacji in situ (FISH) oraz, w niektórych przypadkach, aCGH jest niezbędnym narzędziem rozpoznawania, klasyfikowania i oceny stopnia zaawansowania agresywnych, nieziarniczych chłoniaków B-komórkowych. Technika mikromacierzy CGH (aCGH) była kluczowym elementem wyróżnienia prowizorycznej grupy chłoniaków Burkitt-like z aberracją chromosomu 11q (Burkitt-like lymphoma with 11q aberration – BLL, 11q) w najnowszej klasyfikacji nowotworów układu chłonnego Światowej Organizacji Zdrowia (World Health Organization – WHO) z 2016 r. Omówione zostaną sposoby różnicowania na poziomie cytogenetycznym takich chłoniaków jak: chłoniak Burkitta (Burkitt lymphoma – BL), chłoniak rozlany z dużych komórek B (diffuse large B-cell lymphoma – DLBCL) oraz 2 nowych jednostek klasyfikacji WHO 2016, czyli chłoniaka z komórek B wysokiego stopnia złośliwości z obecnością translokacji MYC i BCL2 i/lub BCL6 (high-grade B-cell lymphoma HGBL, with MYC and BCL2 and/or BCL6 translocations) oraz chłoniaka BLL, 11q.

scholarly journals Aggressive Lymphoma “Sarcoma Mimicker” Originating in the Gluteus and Adductor Muscles: A Case Report and Literature Review

2016 ◽  
Vol 9 ◽  
pp. CCRep.S39052 ◽  
Author(s):  
Sarah A. Elkourashy ◽  
Abdulqadir J. Nashwan ◽  
Syed I. Alam ◽  
Adham A. Ammar ◽  
Ahmed M. El Sayed ◽  
...  
Keyword(s):  
Case Report ◽  
B Cell ◽  
Multidisciplinary Team ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Adductor Muscles ◽  
Large B Cell

Extranodal lymphoma (ENL) occurs in approximately 30%–40% of all patients with non-Hodgkin lymphoma and has been described in almost all organs and tissues. However, diffuse large B-cell lymphoma is the most common histological subtype of non-Hodgkin lymphoma, primarily arising in the retroperitoneal region. In this article, we report a rare case of an adult male diagnosed with primary diffuse large B-cell lymphoma of the gluteal and adductor muscles with aggressive bone involvement. All appropriate radiological and histopathological studies were done for diagnosis and staging. After discussion with the lymphoma multidisciplinary team, it was agreed to start on R-CHOP protocol (rituximab, cyclophosphamide, doxorubicin (Adriamycin), vincristine (Oncovin®), and prednisone) as the standard of care, which was later changed to R-CODOX-M/R-IVAC protocol (rituximab, cyclophosphamide, vincristine (Oncovin®), doxorubicin, and high-dose methotrexate alternating with rituximab, ifosfamide, etoposide, and high-dose cytarabine) due to inadequate response. Due to the refractory aggressive nature of the disease, subsequent decision of the multidisciplinary team was salvage chemotherapy and autologous stem cell transplant. The aim of this case report was to describe and evaluate the clinical presentation and important radiological features of extranodal lymphoma affecting the musculoskeletal system.

scholarly journals Molecular Sub-typing of Diffuse Large B-cell Lymphoma

2021 ◽  
Author(s):  
Thomas Drago
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
Rapid Development ◽  
B Cell Lymphoma ◽  
The United States ◽  
Cellular Level ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is the most common form of Non-Hodgkin Lymphoma (NHL) in adults. Affecting nearly 7 out of every 100,000 people in the United States annually, this hematogenous neoplasm is known for its aggressiveness and rapid development. Being the most common NHL, it has been divided into several subgroups based on pathogenesis and treatment methods. In particular, subtypes such as germinal center, activated B-cell-like, and primary mediastinal diffuse large B-cell lymphomas  have been divided by their uniqueness of pathology at the cellular level. Knowing the numerous cytokines, inflammatory markers, and other microcellular processes that these lymphomas disrupt can help target an effective therapeutic at the disease.

scholarly journals Primary pituitary diffuse large B-cell lymphoma with somatotroph hyperplasia and acromegaly: case report

2017 ◽  
Vol 126 (5) ◽  
pp. 1725-1730 ◽  
Author(s):  
Vijay M. Ravindra ◽  
Amol Raheja ◽  
Heather Corn ◽  
Meghan Driscoll ◽  
Corrine Welt ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Common Type ◽  
Histopathological Diagnosis ◽  
Sellar Lesions ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Persistent Elevation ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and comprises approximately 30% of all lymphomas. Patients typically present with a nonpainful mass in the neck, groin, or abdomen associated with constitutional symptoms. In this report, however, the authors describe a rare case of a 61-year-old woman with hyperprolactinemia, hypothyroidism, and acromegaly (elevation of insulin-like growth factor-1 [IGF-1]) with elevated growth hormone–releasing hormone (GHRH) in whom an MRI demonstrated diffuse enlargement of the pituitary gland. Despite medical treatment, the patient had persistent elevation of IGF-1. She underwent a transsphenoidal biopsy, which yielded a diagnosis of DLBCL with an activated B-cell immunophenotype with somatotroph hyperplasia. After stereo-tactic radiation therapy in combination with chemotherapy, she is currently in remission from her lymphoma and has normalized IGF-1 levels without medical therapy, 8 months after her histopathological diagnosis. This is the only reported case of its kind and displays the importance of a broad differential diagnosis, multidisciplinary evaluation, and critical intraoperative decision-making when treating atypical sellar lesions.

A case of primary breast diffuse large B cell lymphoma

2021 ◽  
Vol 148 (12) ◽  
pp. 102-107
Author(s):  
Trinh Le Huy ◽  
Tran Dinh Anh
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Excisional Biopsy ◽  
Needle Aspiration ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Painless Mass ◽  
Large B Cell

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare non-Hodgkin’s lymphoma with limited data. We here report a case of primary breast diffuse large B-cell lymphoma mimicking breast cancer. A 52-year-old woman had a painless mass in her right breast. Fine needle aspiration cytology and core biopsy were performed which suggested malignant features but could not confirm the specific subtype. Excisional biopsy then was conducted revealing non-Hodgkin lymphoma, which was subsequently confirmed with histopathology and diagnosed as diffuse large B-cell lymphoma (DLBCL). A chest computed tomography scan revealed a 3.5 cm sized breast mass with skin thickening and modest lymphadenopathy in the ipsilateral axilla. The patient received six courses of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab) chemotherapy, then whole breast radiation (30Gy in 15 fractions). At 12 months of follow-up, the patient survives with no evidence of disease. No morbidities occurred in this patient during the follow-up period. We briefly review the current practice pattern in patients with primary breast diffuse large B-cell lymphoma.

Outcome of Diffuse Large B-Cell Lymphoma with First-line Chemotherapy

2021 ◽  
Vol 5 (01) ◽  
pp. 03-09
Author(s):  
Zulfia Zinat Chowdhury ◽  
Tamanna Bahar ◽  
Shaila Rahman ◽  
Salina Haque ◽  
A K M Mynul Islam ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
First Line ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Retrospective Data Analysis ◽  
Significant Difference ◽  
Line Chemotherapy ◽  
Large B Cell

Background: Diffuse Large B-Cell Lymphoma (DLBCL), most common Non-Hodgkin Lymphoma (NHL) variety, is an aggressive, fast-growing form comprising up to 40% of all cases globally. Objective: To observe the treatment outcome of different subtypes of Diffuse Large B-Cell Lymphoma (DLBCL) after first-line chemotherapy and also the association with IHC, presenting age, sex, and IPI score with outcome. Methodology: This is a retrospective data analysis included all DLBCL patients registered in the department of Haematology of National Institute of Cancer Research and Hospital (NICRH) between July 2016 to June 2019. Results: Total 188 cases were included in this study and mean age was 48 years with a Standard deviation of 15 years with Male (69.1%) predominance. We divide the cases into three different entities of DLBCL [Germinal Centre B-cell like (GCB), Non-GCB and others (NOS) among them Non-GCB variety was the prevalent (47.3%) one. After first line   chemotherapy 52.1% complete remission with 7% death was observed in overall outcome. There was no significant difference in outcome among different types of DLBCL after chemotherapy based on Han’s algorithm. Rituximab with CHOP has significantly better outcome than CHOP alone arm (p: 0.021). Conclusion: This limited database study of NICRH will help to ascertain the outcome of DLBCL after first-line chemotherapy in Bangladesh.

scholarly journals Clinical significance of metabolism-related biomarkers in non-Hodgkin lymphoma – MCT1 as potential target in diffuse large B cell lymphoma

2019 ◽  
Vol 42 (3) ◽  
pp. 303-318 ◽  
Author(s):  
Julieta Afonso ◽  
Tatiana Pinto ◽  
Susana Simões-Sousa ◽  
Fernando Schmitt ◽  
Adhemar Longatto-Filho ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Clinical Significance ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Potential Target ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Limited Renal Intravascular Lymphoma: A Case Report and Review of the Literature

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Guillermo Enrique Quintero Vega ◽  
Daniel Osorio ◽  
José Antonio de la Hoz Valle ◽  
Daniela Rodríguez Feria
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Renal Involvement ◽  
B Cell Lymphoma ◽  
Body Images ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Pet Ct ◽  
Low Incidence ◽  
Large B Cell

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. It is characterized by the proliferation of cancerous cells into the intraluminal space of the blood vessels. It has a low incidence rate of 0.095 cases per 1,000,000. The clinical presentation is insidious and unspecific, often delaying the diagnosis. IVLBCL can be diagnosed through body images and histopathology analysis. This neoplasm averages a 60% response rate to current chemotherapy treatment, favoring rituximab, and doxorubicin-based regimen if it is diagnosed in time. Here, we present the case of a 56-year-old man admitted to our hospital with a fever who was eventually diagnosed with IVLBCL. He presented to the consultation with anemia, fever, and splenomegaly. An infection panel, a bone marrow biopsy, and a PET-CT scan were performed and ruled out the possibility of infections and neoplasms. The patient later developed edematous syndrome. As a result, a renal biopsy was performed which tested positive for intravascular large B-cell lymphoma. Currently, the patient has been in complete remission for 33 months. Along with presenting this specific case, we also reviewed previously published cases of IVLBCL to illustrate the renal involvement of this pathology.

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