ABSTRACT
Diffuse large B-cell lymphoma (DLBCL) transformed from follicular lymphoma (FL) (tDLBCL) has been traditionally associated with an aggressive course, but more recent studies have shown longer survivals. The clinical significance of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) is less clear. We compared outcomes of tDLBCL, cDLBCL/FL, and de novo DLBCL (dDLBCL) and then evaluated the impact of double hit (DH) rearrangements (MYC with BCL2 and/or BCL6) in these subgroups' outcomes. The progression free survival (PFS) and overall survival (OS) were not significantly different among the three groups (dDLBCL, tDLBCL, and cDLBCL/FL). The effect of DH on survival was then analyzed in two subgroups: (1) dDLBCL and (2) tDLBCL + cDLBCL/FL. PFS and OS were significantly shorter in lymphomas with DH in each of these two subgroups. We conclude that DH status drives outcomes in all DLBCLs, regardless of their transformation status.
Subject(s)
Cell Transformation, Neoplastic/genetics , Lymphoma, Follicular/mortality , Lymphoma, Large B-Cell, Diffuse/mortality , Neoplasms, Multiple Primary/mortality , Neoplasms, Second Primary/mortality , Aged , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Female , Gene Rearrangement , Humans , Lymphoma, Follicular/complications , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/genetics , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/etiology , Lymphoma, Large B-Cell, Diffuse/genetics , Male , Middle Aged , Neoplasms, Multiple Primary/drug therapy , Neoplasms, Multiple Primary/genetics , Neoplasms, Multiple Primary/pathology , Neoplasms, Second Primary/drug therapy , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/pathology , Progression-Free Survival , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-myc/genetics , Retrospective Studies , Rituximab/therapeutic use , Time FactorsABSTRACT
PURPOSE OF REVIEW: Chronic lymphocytic leukemia (CLL) has multiple current frontline therapy options, including chemoimmunotherapy (CIT) and most recently, ibrutinib. Here, we review the most recent updates in the frontline treatment of CLL, including updates in CIT, updates in targeted therapies, and ongoing clinical trials. RECENT FINDINGS: Ibrutinib was FDA-approved for the upfront treatment of CLL in 2016 after being studied in older patients and those with 17p deletions or TP53 mutations. The introduction of ibrutinib has dramatically changed the treatment paradigm of CLL. Recent updates in CIT include that immunoglobulin heavy chain variable (IGHV) gene mutation status is strongly predictive of response to CIT. Regarding targeted therapy, next-generation BTK and PI3K inhibitors are currently being studied in the upfront treatment of CLL, which may have less toxicity than their first-generation counterparts. Other novel targeted therapies are being studied in the frontline setting, most notably venetoclax including in combinations, with hopes to achieve chemotherapy-free, time-limited treatment options. Multiple key ongoing phase 3 clinical trials will be answering these important clinical questions.
Subject(s)
Immunotherapy/methods , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Chromosome Deletion , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/immunology , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Piperidines , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/immunologyABSTRACT
The bromodomain and extra-terminal (BET) family of proteins are important epigenetic regulators involved in promoting gene expression of critical oncogenes. BET inhibitors have been demonstrated to repress c-Myc expression, and were initially shown to have efficacy in a number of c-Myc-dependent hematologic malignancies. Recent studies have now revealed a broader role for BET inhibitors in hematologic malignancies. In this review, we summarize the efficacy of BET inhibitors in preclinical models of acute leukemia, lymphoma, and multiple myeloma. We also summarize recent results of clinical trials utilizing BET inhibitors in hematologic malignancies, characterize potential resistance mechanisms to BET inhibitors, and discuss potential combination therapies with BET inhibitors in patients with hematologic malignancies.
ABSTRACT
A central question in genomic imprinting is how parental-specific DNA methylation of imprinting control regions (ICR) is established during gametogenesis and maintained after fertilization. At the imprinted Igf2/H19 locus, CTCF binding maintains the unmethylated state of the maternal ICR after the blastocyst stage. In addition, evidence from Beckwith-Wiedemann patients and cultured mouse cells suggests that two Sox-Oct binding motifs within the Igf2/H19 ICR also participate in maintaining hypomethylation of the maternal allele. We found that the Sox and octamer elements from both Sox-Oct motifs were required to drive hypomethylation of integrated transgenes in mouse embryonic carcinoma cells. Oct4 and Sox2 showed cooperative binding to the Sox-Oct motifs, and both were present at the endogenous ICR. Using a mouse with mutations in the Oct4 binding sites, we found that maternally transmitted mutant ICRs acquired partial methylation in somatic tissues, but there was little effect on imprinted expression of H19 and Igf2. A subset of mature oocytes also showed partial methylation of the mutant ICR, which suggested that the Sox-Oct motifs provide some protection from methylation during oogenesis. The Sox-Oct motifs, however, were not required for erasure of paternal methylation in primordial germ cells, which indicated that the oocyte methylation was acquired post-natally. Maternally inherited mutant ICRs were unmethylated in blastocysts, which suggested that at least a portion of the methylation in somatic tissues occurred after implantation. These findings provide evidence that Sox-Oct motifs contribute to ICR hypomethylation in post-implantation embryos and maturing oocytes and link imprinted DNA methylation with key stem cell/germline transcription factors.
Subject(s)
DNA Methylation/genetics , Genomic Imprinting , Insulin-Like Growth Factor II/metabolism , Octamer Transcription Factor-3/metabolism , RNA, Long Noncoding/metabolism , SOXB1 Transcription Factors/metabolism , Alleles , Animals , Binding Sites , Blastocyst/metabolism , CCCTC-Binding Factor , Female , Gene Expression Regulation, Developmental , Germ Cells/metabolism , Insulin-Like Growth Factor II/genetics , Male , Mice , Mutation , Nucleotide Motifs/genetics , Oocytes/metabolism , Protein Binding/genetics , RNA, Long Noncoding/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Repressor Proteins/metabolism , Transcriptional Activation/genetics , TransgenesABSTRACT
The expression of intestinal Niemann-Pick C1-like 1 (NPC1L1) cholesterol transporter has been shown to be elevated in patients with diseases associated with hypercholesterolemia such as diabetes mellitus. High levels of glucose were shown to directly increase the expression of NPC1L1 in intestinal epithelial cells, but the underlying mechanisms are not fully defined. The present studies were, therefore, undertaken to examine the transcriptional regulation of NPC1L1 expression in human intestinal Caco2 cells in response to glucose. Removal of glucose from the culture medium of Caco2 cells for 24 h significantly decreased the NPC1L1 mRNA, protein expression, as well as the promoter activity. Glucose replenishment significantly increased the promoter activity of NPC1L1 in a dose-dependent manner compared with control cells. Exposure of Caco2 cells to nonmetabolizable form of glucose, 3-O-methyl-d-glucopyranose (OMG) had no effect on NPC1L1 promoter activity, indicating that the observed effects are dependent on glucose metabolism. Furthermore, glucose-mediated increase in promoter activity was abrogated in the presence of okadaic acid, suggesting the involvement of protein phosphatases. Glucose effects on several deletion constructs of NPC1L1 promoter demonstrated that cis elements mediating the effects of glucose are located in the region between -291 and +56 of NPC1L1 promoter. Consistent with the effects of glucose removal on NPC1L1 expression in Caco2 cells, 24-h fasting resulted in a significant decrease in the relative expression of NPC1L1 in mouse jejunum. In conclusion, glucose appears to directly modulate NPC1L1 expression via transcriptional mechanisms and the involvement of phosphatase-dependent pathways.
