scholarly journals CS2164 and Venetoclax Show Synergistic Antitumoral Activities in High Grade B-Cell Lymphomas With MYC and BCL2 Rearrangements

2021 ◽  
Vol 11 ◽  
Author(s):  
Delin Yuan ◽  
Genhong Li ◽  
Lian Yu ◽  
Yuelong Jiang ◽  
Yuanfei Shi ◽  
...  
Keyword(s):  
B Cell ◽  
Combined Treatment ◽  
B Cell Lymphoma ◽  
Tumor Burden ◽  
High Grade ◽  
Specific Patient ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway ◽  
Synergistic Cytotoxicity ◽  
Repair Ability

High-grade B-cell lymphoma with concurrent MYC and BCL2 rearrangements (HGBL-DHL) is a rare, aggressive mature B-cell malignancy with a high likelihood of treatment failure following front-line immunochemotherapies. Patients with HGBL-DHL who develop a relapsed or refractory disease have little effective therapeutic strategies and show very poor clinical outcomes, thus calling for development of novel therapies for this specific patient population. In this study, we investigated the preclinical anti-lymphoma efficacies and potential mechanism of action of a novel treatment approach, combining the BCL2 inhibitor venetoclax with CS2164, a new orally active multitarget inhibitor, in HGBL-DHL models. This combination therapy exhibited a robust synergistic cytotoxicity against HGBL-DHL cells, evidenced by cooperatively inducing loss of cell viability and promoting cell apoptosis. Moreover, coadministration of CS2164 and venetoclax resulted in significant superior suppression of HGBL-DHL cell growth and remarkably abrogated tumor burden in a HGBL-DHL-xenografted mouse model. The synergistic lethality of CS2164 and venetoclax in HGBL-DHL cells was associated with induction of DNA damage and impairment of DNA repair ability. Of importance, the combined treatment almost abolished the expression of both BCL2 and MYC, two hallmark proteins of HGBL-DHL, and substantially blunted the activity of PI3K/AKT/mTOR signaling cascade. In addition, MCL1 and BCL-XL, two well-characterized contributors for venetoclax resistance, were significantly lessened in the presence of CS2164 and venetoclax, thus leading to the accumulation of proapoptotic proteins BAX and PUMA and then initiating the intrinsic apoptosis pathway. Taken together, these findings suggest that the regimen of CS2164 and venetoclax is highly effective to eliminate HGBL-DHL cells in the preclinical setting, warranting further clinical investigations of this regimen for the treatment of unfavorable HGBL-DHL patients.

scholarly journals Targeting mitochondrial respiration and the BCL2 family in MYC-associated B-cell lymphoma

2020 ◽  
Author(s):  
Giulio Donati ◽  
Micol Ravà ◽  
Marco Filipuzzi ◽  
Paola Nicoli ◽  
Laura Cassina ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
B Cell ◽  
Complex I ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Grade ◽  
Apoptosis Pathway ◽  
Bcl2 Family ◽  
Molecular Features ◽  
Intrinsic Apoptosis Pathway

AbstractMultiple molecular features, such as activation of specific oncogenes (e. g. MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL). Understanding the relationships between these features and their possible exploitation toward disease classification and therapy remains a major priority in the field. Here, we report that MYC activity in DLBCL is closely correlated with – and most likely a driver of – gene signatures related to Oxidative Phosphorylation (OxPhos). On this basis, we hypothesized that enzymes involved in Oxidative Phosphorylation, and in particular electron-transport chain (ETC) complexes, might constitute tractable therapeutic targets in MYC-associated lymphoma. Indeed, our data show that MYC sensitizes B-cells to IACS-010759, a selective inhibitor of ETC complex I. Mechanistically, IACS-010759 activates an ATF4-driven Integrated Stress Response (ISR), engaging the intrinsic apoptosis pathway through the transcription factor CHOP. In line with these findings, IACS-010759 shows synergy with the BCL2 inhibitor venetoclax against double-hit lymphoma (DHL), a high-grade form of DLBCL with concurrent activation of MYC and BCL2. Similarly, in BCL2-negative lymphoma cell lines, inhibition of the BCL2-related protein Mcl-1 potentiates killing by IACS-010759. Altogether, ETC complex I inhibition engages the ISR to lower the apoptotic threshold in MYC-driven lymphomas and, in combination with select BCL2-family inhibitors, provides a novel therapeutic principle against this aggressive DLBCL subset.Statement of significanceThis work points to OxPhos as a key MYC-activated process and a tractable therapeutic target toward personalized treatment of high-grade DLBCL, providing strong context-dependent cooperation with BH3-mimetic compounds.

Taking control of the female fertile lifespan: a key role for Bcl-2 family proteins

2016 ◽  
Vol 28 (7) ◽  
pp. 864 ◽  
Author(s):  
Seng H. Liew ◽  
Kavitha Vaithiyanathan ◽  
Karla J. Hutt
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Female Fertility ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Primordial Follicles ◽  
Intrinsic Apoptosis Pathway ◽  
Reproductive Life ◽  
The Relationship

Precisely how the length of the female fertile lifespan is regulated is poorly understood and it is likely to involve complex factors, one of which is follicle number. Indeed, the duration of female fertility appears to be intimately linked to the number of available oocytes, which are stored in the ovary as primordial follicles. There is mounting evidence implicating the intrinsic apoptosis pathway, which is controlled by members of the B-cell lymphoma-2 (BCL-2) family, as a key regulator of the number of primordial follicles established in the ovary at birth and maintained throughout reproductive life. Consequently, the pro- and anti-apoptotic BCL-2 family proteins are emerging as key determinants of the length of the female fertile lifespan. This review discusses the relationship between the intrinsic apoptosis pathway, follicle number and length of the female fertile lifespan.

scholarly journals Combination of CS2164 and Venetoclax Shows Synergistic Antitumor Effect in High-Grade B-Cell Lymphomas with ConcomitantMYCandBCL2Rearrangements

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-41
Author(s):  
Manman Deng ◽  
Delin Yuan ◽  
Genhong Li ◽  
Yuelong Jiang ◽  
Qinwei Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
High Grade ◽  
Specific Patient ◽  
Bcl2 Family ◽  
Mitochondrial Membrane Depolarization ◽  
Orally Active

High-grade B-cell lymphoma with concurrentMYCandBCL2rearrangements (HGBCL-DHL) is a rare and aggressive B-cell disorder with a high likelihood of nonresponsiveness to the front-line immunochemotherapy. Patients with HGBCL-DHL who develop a recurrent or progressive disease have limited effective therapeutics and show very poor clinical outcomes. Therefore, it calls for the development of novel targeted therapies for this specific patient populations. In this study, we showed that combination of BCL2 inhibitor venetoclax and CS2164, a novel orally active multitarget inhibitor, is a potent therapeutic strategy against HGBCL-DHL in the preclinical setting. BCL2rearrangement, a hallmark feature of HGBCL-DHL, often results in increased BCL2 protein that counteracts the proapoptotic proteins of BCL2 family, and thus blocks cell death. BCL2 blockage with venetoclax shows promising clinical responses in various human malignancies. However, resistance to venetoclax takes place following its continuous administration, suggesting that venetoclax should combine with other agents to prevent disease progression. CS2164 is originally developed by China and designed to perturb three key characteristics of neoplasms: tumor angiogenesis, cell mitosis and chronic inflammation. Our previous study demonstrated that CS2164 exerted potently antilymphoma activities in MYC-driven lymphomas, providing evidence that CS2164 could potentiate the effect of venetoclax for MYC/BCL2 driven HGBCL-DHL. In the present work, we first observed that both venetoclax and CS2164 as single agent reduced the capability of cell proliferation in HGBCL-DHL cell lines. Next, we found that CS2164 synergized with venetoclax to suppress cell proliferation and trigger cell apoptosis in HGBCL-DHLin vitro. More importantly, when compared with each single drug groups, coadministration of venetoclax and CS2164 resulted in superior suppression of HGBCL-DHL cell growth and remarkably abrogated tumor burden in a HGBCL-DHL-xenografted mouse model. The synergistic lethality of venetoclax and CS2164 towards HGBCL-DHL cells was associated with the modulation of multiple molecular mechanisms. The underlying mechanisms for the synergy of the two drugs included the blockade of Rad51 recombinase-dependent DNA repair, the perturbation of the delicate balance of BCL2 family proteins that induced mitochondrial membrane depolarization and subsequently led to the proapoptotic effect, as well as the inhibition of PI3K/AKT/mTOR pathway and MYC expression. In summary, these findings suggest that the regimen of CS2164 and venetoclax combination is highly effective to eliminate HGBCL-DHL cellsin vitroandin vivoand thus provide a rational treatment paradigm to strip HGBCL-DHL of its protection fromMYCandBCL2rearrangements. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: CS2164 originally developed by China is a novel orally active multitarget inhibitor that is evaluating in clinical trials against multiple solid tumors.

Small-Molecule XIAP Antagonist Restores Caspase-9-Mediated Apoptosis in XIAP-Positive Diffuse Large B-Cell Lymphoma Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 803-803 ◽  
Author(s):  
Saskia A.G.M. Cillessen ◽  
John C. Reed ◽  
Clemencia Pinilla ◽  
Chris J.L.M. Meijer ◽  
Erik Hooijberg ◽  
...  
Keyword(s):  
B Cell ◽  
Small Molecule ◽  
Mononuclear Cells ◽  
B Cell Lymphoma ◽  
Caspase 9 ◽  
Lymphoma Cells ◽  
Apoptosis Pathway ◽  
Expression Levels ◽  
Intrinsic Apoptosis Pathway ◽  
Large B Cell

Abstract Clinical outcome in patients with diffuse large B-cell lymphomas (DLBCL) is correlated with expression of inhibitors of the intrinsic apoptosis pathway, including XIAP. XIAP suppresses apoptosis through inhibiting active caspases-3, -7 and -9. In this study we investigated if the small-molecule XIAP antagonist 1396–12 induces cell death in cultured lymphoma cells of DLBCL patients and whether it is possible to predict whether a DLBCL will be sensitive to the XIAP antagonist. Treatment with this XIAP antagonist resulted in induction of apoptosis in 16 of 20 tested DLBCL samples. Sensitivity to the XIAP antagonist was observed in both chemotherapy refractory and responsive DLBCL, but did not affect peripheral blood mononuclear cells and tonsil germinal center B-cells from healthy donors. XIAP antagonist-sensitive cases were characterized by high expression levels of XIAP and relatively low expression levels of Bcl-2. In addition, we found that XIAP antagonist sensitive lymphomas are characterized by constitutive caspase-9 activation and that the apoptosis inducing effect of the XIAP antagonist depends on this constitutive caspase 9 activity. These data indicate that the small-molecule XIAP antagonist can induce apoptosis in DLBCL cells by restoring caspase 9 mediated apoptosis and therefore should be considered for possible development as a therapy for these patients. In vitro sensitivity to the XIAP antagonist can be predicted based on biological markers suggesting the possibility of pre-defining patients most likely to benefit from XIAP antagonist therapy.

Polymorphisms in key regulator genes of the intrinsic apoptosis pathway in risk and clinical presentation of diffuse large B-cell lymphoma

2016 ◽  
Vol 35 (4) ◽  
pp. 911-913
Author(s):  
Angelo Borsarelli Carvalho Brito ◽  
Marcia Torresan Delamain ◽  
Cristiane de Oliveira ◽  
Carmino Antonio de Souza ◽  
José Vassallo ◽  
...  
Keyword(s):  
B Cell ◽  
Clinical Presentation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Large B Cell Lymphoma ◽  
Intrinsic Apoptosis Pathway ◽  
Regulator Genes ◽  
Large B Cell

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.

A Challenging Case of A Myeloid Sarcoma Misdiagnosed as High Grade B-Cell Lymphoma

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S97-S97
Author(s):  
A Herrmann ◽  
B Mai ◽  
S Elzamly ◽  
A Wahed ◽  
A Nguyen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Myeloid Sarcoma ◽  
Proliferation Index ◽  
High Grade ◽  
Cell Markers ◽  
Thoracolumbar Region ◽  
The Right

Abstract Introduction/Objective A 46-year-old female presented with severe back pain associated with progressive bilateral lower extremity weakness and paresthesia, urinary retention, and constipation. Computed tomography revealed a retroperitoneal mass encasing the right psoas muscle, obstructing the right kidney, and extending to the thoracolumbar region resulting in severe spinal compression. An epidural tumor resection was subsequently performed at an outside hospital. Methods Histological sections showed sheets of blastoid neoplastic cells with intermediate to large nuclei, irregular membranes, fine chromatin, and prominent nucleoli. Immunohistochemical stains showed that these cells were positive for CD43, CD79a (weak, focal), BCL2, C-MYC, and PAX5 (weak, focal) and negative for CD10, CD20, CD30, ALK1, BCL6, MUM1, and Tdt. The Ki-67 proliferation index was 75-80%. With this immunophenotype, this patient was diagnosed with a high grade B-cell lymphoma and transferred to our institution for further work-up. On review of the slides, further immunohistochemical testing was requested which revealed positivity for CD117 and myeloperoxidase (MPO). Results The overall morphological and immunophenotypical features are most compatible with myeloid sarcoma (MS) with aberrant expression of B-cell markers and this patient’s diagnosis was amended. Interestingly, the patient’s bone marrow examination only showed 2% myeloblasts with left shifted granulocytosis and concurrent fluorescence in situ hybridization (FISH) studies were negative. Conclusion A literature review showed that 40-50% of MS are misdiagnosed as lymphoma. MS can frequently stain with B-cell or T-cell markers, as seen in this case, which makes it challenging for an accurate diagnosis and sub- classification. In addition, our case is interesting in that there was only extramedullary presentation without bone marrow involvement. Typically, MS develops after the diagnosis of acute myeloid leukemia (AML) with an incidence of 3–5% after AML. It can also manifest de novo in healthy patients, who then go on to develop AML months to years later. Therefore, this patient will require close follow-up.

scholarly journals High‐grade B‐cell lymphoma developed during the treatment of chronic myeloid leukemia with bosutinib

2021 ◽  
Author(s):  
Teruhito Takakuwa ◽  
Ryota Sakai ◽  
Shiro Koh ◽  
Hiroshi Okamura ◽  
Satoru Nanno ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
B Cell ◽  
Myeloid Leukemia ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Grade
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