PURPOSE: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2. A BCL2-targeting drug, venetoclax, has promising anticancer activity in MCL. We analyzed molecular mechanisms of venetoclax resistance in MCL cells and tested strategies to overcome it. EXPERIMENTAL DESIGN: We confirmed key roles of proapoptotic proteins BIM and NOXA in mediating venetoclax-induced cell death in MCL. Both BIM and NOXA are, however, differentially expressed in cell lines compared with primary cells. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, deletions of BIM gene harbored by three commonly used MCL cell lines (JEKO-1, MINO, and Z138) were not found by array comparative genomic hybridization using a validation set of 24 primary MCL samples. RESULTS: We demonstrated that MCL1 and NOXA play important roles in mediating resistance to venetoclax. Consequently, we tested an experimental treatment strategy based on cotargeting BCL2 with venetoclax and MCL1 with a highly specific small-molecule MCL1 inhibitor S63845. The combination of venetoclax and S63845 demonstrated synthetic lethality in vivo on a panel of five patient-derived xenografts established from patients with relapsed MCL with adverse cytogenetics. CONCLUSIONS: Our data strongly support investigation of venetoclax in combination with S63845 as an innovative treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds.

• MeSH
• bicyklické sloučeniny heterocyklické farmakologie   MeSH
• chemorezistence MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   metabolismus   patologie   MeSH
• lymfom z plášťových buněk farmakoterapie   metabolismus   patologie   MeSH
• myši inbrední NOD MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protein MCL-1 antagonisté a inhibitory   metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• protoonkogenní proteiny c-bcl-2 antagonisté a inhibitory   metabolismus   MeSH
• pyrimidiny farmakologie   MeSH
• sulfonamidy farmakologie   MeSH
• synergismus léků * MeSH
• thiofeny farmakologie   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Lecithin:retinol acyltransferase (LRAT) is the major enzyme responsible for retinol esterification in the mammalian body. LRAT exhibits specific activity in the cells with active retinol metabolism where it converts retinols into retinyl esters, which represents the major storage form of retinol. Besides hepatic stellate cells in the liver, LRAT appears to have a key physiologic role in several other tissues. In this study, we generated a transgenic reporter mouse expressing green fluorescence protein (EGFP) under the control of region containing -1166 bps from promoter upstream from the putative transcriptional start site and 262 bps downstream of this start. Transgenic reporter mice exhibited specific expression in eyes and testes. In eyes, expression of EGFP-reporter is found in lens and lens epithelium and fibers from embryo to adulthood. In testes, LRAT-EGFP reporter is expressed both in Sertoli and in spermatocytes marking initiation of spermatogenesis in prepubertal mice. Our data show that the examined LRAT regulatory region is sufficient to achieve strong and selective expression in the eye and testes but not in liver and other organs.

• MeSH
• acyltransferasy genetika   MeSH
• epitel metabolismus   MeSH
• genetická transkripce genetika   MeSH
• genotyp MeSH
• meióza genetika   MeSH
• myši transgenní MeSH
• myši MeSH
• oční čočka metabolismus   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• regulace genové exprese enzymů genetika   MeSH
• Sertoliho buňky metabolismus   MeSH
• spermatocyty ultrastruktura   MeSH
• spermatogeneze MeSH
• testis metabolismus   MeSH
• vitamin A metabolismus   MeSH
• vývojová regulace genové exprese genetika   MeSH
• zelené fluorescenční proteiny MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH