Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium.
Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol. 2019 Sep 09;:JCO1900743 Authors: Rosenwald A, Bens S, Advani R, Barrans S, Copie-Bergman C, Elsensohn MH, Natkunam Y, Calaminici M, Sander B, Baia M, Smith A, Painter D, Pham L, Zhao S, Ziepert M, Jordanova ES, Molina TJ, Kersten MJ, Kimby E, Klapper W, Raemaekers J, Schmitz N, Jardin F, Stevens WBC, Hoster E, Hagenbeek A, Gribben JG, Siebert R, Gascoyne RD, Scott DW, Gaulard P, Salles G, Burton C, de Jong D, Sehn LH, Maucort-Boulch D Abstract PURPOSE: MYC rearrangement (MYC-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC-R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene. METHODS: The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybr...
Publication date: October 2019Source: Clinical Lymphoma Myeloma and Leukemia, Volume 19, Issue 10, SupplementAuthor(s): M Hasib Sidiqi, Abdullah S. Al Saleh, Nelson Leung, Mohammed Aljama, Dragan Jevremovic, Wilson Gonsalves, Francis Buadi, Taxiarchis Kourelis, Rahma Warsame, Eli Muchtar, Miriam Hobbs, Martha Lacy, David Dingli, Ronald Go, Suzanne Hayman, S.Vincent Rajkumar, Shaji Kumar, Angela Dispenzieri, Rafael Fonseca, Morie A. Gertz
Multiple myeloma (MM) is characterised by paraprotein (PP) and/or serum free light chain (SFLC) production, a hypoxic tumour microenvironment (TME) and increased cellular stress. Glucose-regulated protein 78 (GRP78), an endoplasmic reticulum stress-inducible molecular chaperone, is upregulated at times of cellular stress and acts to limit proteotoxicity and promote cell survival. Translocation of GRP78 to the cell surface (csGRP78) and interaction with cell signalling and survival pathways is emerging as a critical step providing tumour cells with a survival advantage.
Multiple myeloma (MM) is a genetically complex and heterogeneous disease with multiple genomic events associated with tumor development and progression.Chromosomal translocations into the immunoglobulin heavy-chain (IgH) locus on 14q32 are the main primary events, occurring in about 50% of total MM cases.Currently, there are five main chromosomal translocation partners involving with immunoglobulin heavy-chain (IgH), including t(4;14), t(6;14), t(11;14), t(14;16) and t(14;20). However, IgH translocation with undefined partner genes can still be found in 15% of all newly-diagnosed MM (NDMM) patient, and little is known about their survival.
B-cell receptor (BCR) and toll-like receptor (TLR) pathway activation are key drivers of pro-survival signaling in many B-cell and plasma cell malignancies. Both pathways are notable for their activation of common cascades that include BTK, PI3K/AKT, MAPK1 and MAPK3 (ERK1 and ERK2 at the protein level) signaling, as well as the activation and nuclear translocation of nuclear factor kappa-B (NFkB). In Waldenstrom's Macroglobulinemia (WM), the TLR pathway is driven by activating mutations in MYD88 that are found in 95-97% of patients.
Venetoclax is a B cell lymphoma 2 (BCL-2) inhibitor active in multiple myeloma, particularly those harboring t(11;14) associated with high BCL-2 expression. Approximately 50% of patients with immunoglobulin light chain (AL) amyloidosis have t (11;14), making venetoclax a suitable agent to consider in this rare disease. We aimed to identify the safety and efficacy of venetoclax in patients with AL amyloidosis.
Multiple Myeloma (MM), characterized by the uncontrolled proliferation of malignant plasma cells in the bone marrow, occurs mainly in the elderly population. Recurrent chromosomal translocations are central to the pathogenesis of MM, with t(4;14) being the second-most common and associated with poor prognosis. The histone methyltransferase (HMTase) MMSET is overexpressed in MM as a result of the t(4;14) translocation. MMSET is capable of producing 3 major isoforms, MMSET II, REIIBP and MMSET I. MMSET II encodes the full-length protein of 1365 amino acids and possesses HMTase activity for H3K36 and H4K20.
DNA methyltransferases (DNMTs) including DNMT1, DNMT3A and DNMT3B, catalyze the transfer of methyl groups to cytosine position 5, and play an important role in epigenetic regulation, which could be involved in pathogenesis of multiple myeloma (MM). Active DNA demethylation occurs during 5-methylcytosine through TET (Ten Eleven Translocation) enzyme-mediated oxidation removal, and this process is necessary for the epigenetic reprograming of genes and is directly involved in tumor progression.
ConclusionMAF deletion was more frequent than MAF translocation with IgH in patients with MM and was more commonly observed in women. Moreover, MAF deletion was often combined with 13q, FGFR3, and IgH deletion. MAF deletion did not influence prognosis in patients with MM who were given a bortezomib-based chemotherapy regimen.
Conclusions This review describes how leukocyte-heparanase can be a double-edged sword in tumor progression; it can enhance tumor immune surveillance and tumor cell clearance, but also promote tumor survival and growth. We also discuss the potential of using heparanase in leukocyte therapies against tumors, and the effects of heparanase inhibitors on tumor progression and immunity. We are just beginning to understand the influence of heparanase on a pro/anti-tumor immune response, and there are still many questions to answer. How do the pro/anti-tumorigenic effects of heparanase differ across different cancer types? Does...
In this study we adopted an all-in-one method. Primers designed according to the two gRNA sequences and the tracRNA-U6 vector sequences were used to produce a gRNA1-tracRNA-U6-gRNA2 fragment. Then the proper fragment was ligated into the lentiCRISPRv2 vector and verified by sequencing. Lentiviral Packaging and Stable Cell Line Screening The constructed eukaryotic expression vector and gene knockdown vector were transfected into the 293T cells with the packaging plasmids psPAX2 and pMD2.G using Lipofectamine 2000 (Thermo Fisher, Massachusetts, USA). The lentivirus was harvested 48 h after transfection, and the lentivirus ...