ABSTRACT
PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains the activity of the PI3K/AKT/mTOR pathway and glycolysis in B-cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B-cell lymphomas and validate it as an attractive and previously unrecognized target in oncology.
Subject(s)
DNA-Binding Proteins/metabolism , Transcription Factors/metabolism , Animals , Apoptosis/genetics , Apoptosis/physiology , Blotting, Western , Cell Survival/genetics , Cell Survival/physiology , Chromatin Immunoprecipitation , Computational Biology , DNA-Binding Proteins/genetics , Female , Flow Cytometry , Gene Expression Regulation/genetics , Gene Expression Regulation/physiology , Humans , Lymphoma/genetics , Lymphoma/metabolism , Mice , Mice, SCID , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Random Allocation , Transcription Factors/genetics , Transcriptome/geneticsABSTRACT
Holoprosencephaly (HPE) is a congenital forebrain defect often associated with embryonic lethality and lifelong disabilities. Currently, therapeutic and diagnostic options are limited by lack of knowledge of potential disease-causing mutations. We have identified a new mutation in the PRDM15 gene (C844Y) associated with a syndromic form of HPE in multiple families. We demonstrate that C844Y is a loss-of-function mutation impairing PRDM15 transcriptional activity. Genetic deletion of murine Prdm15 causes anterior/posterior (A/P) patterning defects and recapitulates the brain malformations observed in patients. Mechanistically, PRDM15 regulates the transcription of key effectors of the NOTCH and WNT/PCP pathways to preserve early midline structures in the developing embryo. Analysis of a large cohort of patients with HPE revealed potentially damaging mutations in several regulators of both pathways. Our findings uncover an unexpected link between NOTCH and WNT/PCP signaling and A/P patterning and set the stage for the identification of new HPE candidate genes.
Subject(s)
Cell Polarity , DNA-Binding Proteins/genetics , Holoprosencephaly/genetics , Loss of Function Mutation/genetics , Receptors, Notch/metabolism , Transcription Factors/genetics , Wnt Signaling Pathway , Animals , Body Patterning/genetics , Brain/abnormalities , Brain/embryology , Cell Polarity/genetics , Cohort Studies , Embryo, Mammalian/abnormalities , Embryo, Mammalian/metabolism , Female , Gene Deletion , Gene Expression Regulation, Developmental , Humans , Mice , Neural Plate/metabolism , Pregnancy , Transcription, Genetic , Zinc FingersABSTRACT
Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Ethylenediamines/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Pyrroles/pharmacology , RNA Splicing/drug effects , RNA, Neoplasm/metabolism , Animals , Antineoplastic Agents/pharmacokinetics , Catalysis , Enzyme Inhibitors/pharmacokinetics , Ethylenediamines/pharmacokinetics , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Humans , K562 Cells , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Mice, Inbred C57BL , Mice, Transgenic , Protein-Arginine N-Methyltransferases/genetics , Protein-Arginine N-Methyltransferases/metabolism , Pyrroles/pharmacokinetics , RNA, Neoplasm/genetics , Repressor Proteins/antagonists & inhibitors , Repressor Proteins/metabolism , THP-1 Cells , Tumor Cells, Cultured , U937 Cells , Xenograft Model Antitumor AssaysABSTRACT
STAT4 polymorphism, rs7574865 is linked to various autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Its T minor allele is associated with higher STAT4 mRNA and protein expression, indicating a stronger skewed immune response than the norm. Although widely studied in autoimmune disease patients and the general population, its effect on immunocompromised subjects is still unknown. Especially in situations, i.e. post-hematopoietic stem cell transplantation (post-HSCT), where control of the immune response is crucial. Hence, this study investigates if the presence of the T minor allele in donors would affect immunological response and clinical outcomes post-HSCT. Samples from 161 pediatric patients who underwent allogeneic HSCT for acute leukemia and showed complete chimerism by donor cells were obtained. Six clinical outcomes were investigated; hepatic veno-occlusive disease, acute graft-vs-host disease, chronic graft-vs-host disease, cytomegalovirus (CMV) infection, relapse and overall survival. The TT genotype was found to be significant in the occurrence of CMV infection (P=0.049), showing higher incidence of CMV infection compared to the others. Multivariate analysis confirmed that association of the TT genotype is independent from other variables in CMV infection occurrence (P=0.010). This is the first study on STAT4 polymorphism rs7574865 in allogeneic HSCT as well as immunocompromised patients. As the TT genotype is associated with autoimmune diseases, our results seem at a paradox with current evidence hinting at a different role of STAT4 in normal circumstances versus immunocompromised patients. Further investigation is needed to elicit the reason behind this and discover novel applications for better post-transplant outcomes.
