Venetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient-derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status.

• MeSH
• apoptóza účinky léků   MeSH
• benzothiazoly MeSH
• bicyklické sloučeniny heterocyklické * farmakologie   terapeutické užití   MeSH
• chemorezistence * MeSH
• isochinoliny MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protein bcl-X * metabolismus   antagonisté a inhibitory   MeSH
• protein BCL2L11 * metabolismus   genetika   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   antagonisté a inhibitory   MeSH
• sulfonamidy * farmakologie   terapeutické užití   MeSH
• synergismus léků MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• A-1155463 MeSH Prohlížeč
• BCL2L1 protein, human MeSH Prohlížeč
• benzothiazoly MeSH
• bicyklické sloučeniny heterocyklické * MeSH
• isochinoliny MeSH
• protein bcl-X * MeSH
• protein BCL2L11 * MeSH
• protinádorové látky MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• sulfonamidy * MeSH
• venetoclax MeSH Prohlížeč

Non-Hodgkin lymphomas (NHL) represent the most common hematologic malignancies. Patient-derived xenografts (PDXs) are used for various aspects of translational research including preclinical in vivo validation of experimental treatment approaches. While it was repeatedly demonstrated that PDXs keep majority of somatic mutations with the primary lymphoma samples, from which they were derived, the composition of PDX tumor microenvironment (TME) has not been extensively studied. We carried out a comparative genetic and histopathological study of 15 PDX models derived from patients with various types of NHL including diffuse large B-cell lymphoma (DLBCL; n = 7), Burkitt lymphoma (BL; n = 1), mantle cell lymphoma (MCL; n = 2), and peripheral T-cell lymphomas (PTCL; n = 5). Whole exome sequencing (WES) of the PDXs and primary lymphoma cells was implemented in 13 out of 15 cases with available DNA samples. Standard immunohistochemistry (IHC) was used to analyze the composition of PDX TME. WES data confirmed that PDXs maintained the genetic heterogeneity with the original primary lymphoma cells. In contrast, IHC analysis revealed the following recurrently observed alterations in the composition of PDX tumors: more blastoid lymphoma cell morphology, increased proliferation rate, lack of non-malignant cellular components including T cells and (human or murine) macrophages, and significantly lower intratumoral microvessel density and microvessel area composed of murine vessels. In addition, PDX tumors derived from T-NHL displayed additional differences compared to the primary lymphoma samples including markedly lower desmoplasia (i.e., the extent of both reticular and collagen fibrosis), loss of expression of cytotoxic granules (i.e., perforin, TIA, granzyme B), or loss of expression of T-cell specific antigens (i.e., CD3, CD4, CD8). Our data suggest that despite keeping the same genetic profiles, PDX models of aggressive NHL do not recapitulate the microenvironmental heterogeneity of the original lymphomas. These findings have implications on the relevance of PDX models in the context of preclinical research.

• MeSH
• difúzní velkobuněčný B-lymfom * MeSH
• dospělí MeSH
• heterografty MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové mikroprostředí MeSH
• protinádorové látky * MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protinádorové látky * MeSH

The pro-survival MCL1 protein is overexpressed in many cancers, including B-cell non-Hodgkin lymphomas (B-NHL). S63845 is a highly specific inhibitor of MCL1. We analyzed mechanisms of sensitivity/resistance to S63845 in preclinical models of diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. Annexin V-based cytotoxic assays, Western blot analysis, protein co-immunoprecipitation, and cell clones with manipulated expression of BCL2 family proteins were used to analyze mechanisms of sensitivity to S63845. Experimental in vivo therapy with S63845 and/or venetoclax was performed using patient-derived xenografts (PDX) of treatment-refractory B-NHL. A subset of DLBCL and majority of Burkitt lymphoma cell lines were sensitive to S63845. The level of BCL2 protein expression was the major determinant of resistance to S63845: BCL2 serves as a buffer for pro-apoptotic proteins released from MCL1 upon exposure to S63845. While BCL2-negative lymphomas were effectively eliminated by single-agent S63845, its combination with venetoclax was synthetically lethal in BCL2-positive PDX models. Concerning MCL1, both, the level of MCL1 protein expression, and its occupational status represent key factors mediating sensitivity to S63845. In contrast to MCL1-BIM/BAK1 complexes that prime lymphoma cells for S63845-mediated apoptosis, MCL1-NOXA complexes are associated with S63845 resistance. In conclusion, MCL1 represents a critical survival molecule for most Burkitt lymphomas and a subset of BCL2-negative DLBCLs. The level of BCL2 and MCL1 expression and occupational status of MCL1 belong to the key modulators of sensitivity/resistance to S63845. Co-treatment with venetoclax can overcome BCL2-mediated resistance to S63845, and enhance efficacy of MCL1 inhibitors in BCL2-positive aggressive B-NHL.

• MeSH
• apoptóza MeSH
• Burkittův lymfom genetika   mortalita   MeSH
• difúzní velkobuněčný B-lymfom genetika   mortalita   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• protein MCL-1 metabolismus   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BCL2 protein, human MeSH Prohlížeč
• MCL1 protein, human MeSH Prohlížeč
• protein MCL-1 MeSH
• protoonkogenní proteiny c-bcl-2 MeSH

The ability to inhibit mitochondrial apoptosis is a hallmark of B-cell non-Hodgkin lymphomas (B-NHL). Activation of mitochondrial apoptosis is tightly controlled by members of B-cell leukemia/lymphoma-2 (BCL-2) family proteins via protein-protein interactions. Altering the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins leads to apoptosis evasion and extended survival of malignant cells. The pro-survival BCL-2 proteins: B-cell leukemia/lymphoma-2 (BCL-2/BCL2), myeloid cell leukemia-1 (MCL-1/MCL1) and B-cell lymphoma-extra large (BCL-XL/BCL2L1) are frequently (over)expressed in B-NHL, which plays a crucial role in lymphoma pathogenesis, disease progression, and drug resistance. The efforts to develop inhibitors of anti-apoptotic BCL-2 proteins have been underway for several decades and molecules targeting anti-apoptotic BCL-2 proteins are in various stages of clinical testing. Venetoclax is a highly specific BCL-2 inhibitor, which has been approved by the US Food and Drug Agency (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) and is in advanced clinical testing in other types of B-NHL. In this review, we summarize the biology of BCL-2 proteins and the mechanisms of how these proteins are deregulated in distinct B-NHL subtypes. We describe the mechanism of action of BH3-mimetics and the status of their clinical development in B-NHL. Finally, we summarize the mechanisms of sensitivity/resistance to venetoclax.

• Klíčová slova
• B-cell leukemia/lymphoma-2 (BCL-2), apoptosis, non-Hodgkin lymphomas (NHL), venetoclax,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20th century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients' outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL.

• Klíčová slova
• chemotherapy, drug resistance, non-Hodgkin lymphomas, targeted agents,
• MeSH
• chemorezistence * MeSH
• individualizovaná medicína MeSH
• lidé MeSH
• nádorové biomarkery metabolismus   MeSH
• nehodgkinský lymfom * klasifikace   metabolismus   patologie   terapie   MeSH
• protinádorové látky škodlivé účinky   terapeutické užití   MeSH
• záchranná terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• nádorové biomarkery MeSH
• protinádorové látky MeSH

Mantle cell lymphoma (MCL) is a heterogeneous malignancy with a broad spectrum of clinical behavior from indolent to highly aggressive cases. Despite the fact that MCL remains in most cases incurable by currently applied immunochemotherapy, our increasing knowledge on the biology of MCL in the last two decades has led to the design, testing, and approval of several innovative agents that dramatically changed the treatment landscape for MCL patients. Most importantly, the implementation of new drugs and novel treatment algorithms into clinical practice has successfully translated into improved outcomes of MCL patients not only in the clinical trials, but also in real life. This review focuses on recent advances in our understanding of the pathogenesis of MCL, and provides a brief survey of currently used treatment options with special focus on mode of action of selected innovative anti-lymphoma molecules. Finally, it outlines future perspectives of patient management with progressive shift from generally applied immunotherapy toward risk-stratified, patient-tailored protocols that would implement innovative agents and/or procedures with the ultimate goal to eradicate the lymphoma and cure the patient.

• Klíčová slova
• B-cell receptor signaling, cell cycle, mantle cell lymphoma,
• MeSH
• buněčný cyklus účinky léků   genetika   MeSH
• chemorezistence MeSH
• cílená molekulární terapie * metody   MeSH
• genetická variace MeSH
• klonální evoluce účinky léků   genetika   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• lymfom z plášťových buněk farmakoterapie   etiologie   metabolismus   mortalita   MeSH
• náchylnost k nemoci MeSH
• nádorové biomarkery antagonisté a inhibitory   MeSH
• prognóza MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• receptory antigenů B-buněk metabolismus   MeSH
• recidiva MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• nádorové biomarkery MeSH
• protinádorové látky MeSH
• receptory antigenů B-buněk MeSH