ABSTRACT
AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations.
Subject(s)
Gene Expression Regulation, Leukemic/physiology , Homeodomain Proteins/metabolism , Isocitrate Dehydrogenase/metabolism , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , MicroRNAs/metabolism , Animals , Carcinogenesis/genetics , Carcinogenesis/pathology , Cell Line, Tumor , Female , Gene Expression Regulation, Leukemic/genetics , Genotype , Homeodomain Proteins/genetics , Humans , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/genetics , Male , Mice , MicroRNAs/genetics , Mutation/geneticsABSTRACT
This paper elucidates the phytoremediation potential of water hyacinth (Eichhornia crassipes [Mart.] Solms) for TN and TP rich industrial wastewaters determined for 15 weeks under different set-ups of 2-fold (56 TN mg/l and 15.4 TP mg/l), 1-fold, 1/2-fold, 1/4-fold and 1/8-fold and a control with no nutrients in duplicate. A mass balance was conducted to evaluate the phytoremediation efficiencies and to identify the key mechanisms of nutrient removal from the wastewaters. Our results manifested that water hyacinth is a promising candidate for a batch removal of TN and TP from wastewaters. 100% removal of both TN and TP was observed at the end of the 9th week in all the set-ups mainly due to assimilation and the period between 6-9weeks became the optimum period after which complete harvesting is recommended. Plants having an age of 6 weeks are ideal to commence the free-floating wetland and 21 days hydraulic retention time (HRT) is recommended for optimum removal of TN and TP. Assimilation and denitrification were the key mechanisms of TN removal while assimilation and sorption became the prominent mechanisms in the removal of TP from wastewaters.
