ABSTRACT
In this study, we show the high frequency of spontaneous γδ T-cell leukemia (T-ALL) occurrence in mice with biallelic deletion of enhancer of zeste homolog 2 (Ezh2). Tumor cells show little residual H3K27 trimethylation marks compared with controls. EZH2 is a component of the PRC2 Polycomb group protein complex, which is associated with DNA methyltransferases. Using next-generation sequencing, we identify alteration in gene expression levels of EZH2 and acquired mutations in PRC2-associated genes (DNMT3A and JARID2) in human adult T-ALL. Together, these studies document that deregulation of EZH2 and associated genes leads to the development of mouse, and likely human, T-ALL.
Subject(s)
DNA-Binding Proteins/metabolism , Histone-Lysine N-Methyltransferase/metabolism , Leukemia-Lymphoma, Adult T-Cell/metabolism , Transcription Factors/metabolism , Acute Disease , Animals , DNA-Binding Proteins/genetics , Enhancer of Zeste Homolog 2 Protein , Histone-Lysine N-Methyltransferase/genetics , Humans , Leukemia-Lymphoma, Adult T-Cell/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Polycomb Repressive Complex 2 , Polycomb-Group Proteins , Protein Binding , Repressor Proteins/genetics , Repressor Proteins/metabolism , Transcription Factors/geneticsABSTRACT
Chronic graft-versus-host disease (cGVHD) is a common and potentially lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT). cGVHD as well as the transplant procedure itself (chemotherapy with or without radiotherapy) can lead to the degradation of connective tissue components such as elastin and collagen. The catabolism of these structural proteins releases desmosine (DES), lysylpyridinoline (LP), hydroxylysylpyridonoline (HP), and related pyridinium-based cross-linkers analogues that could represent potential biomarkers for cGVHD. This study reports the development of a sensitive liquid chromatography/tandem mass spectrometry method for the simultaneous analysis of N-propyl derivatives of DES, HP, and LP. The concentrations of free and total forms of urinary DES, HP, and LP were determined using synthetic deuterated internal standards. This method enabled accurate quantitation of these pyridinium-based cross-linkers from as little as 100 microL of urine with detection limits of 0.03-0.10 ng/mL. These compounds were analyzed in urine samples from three groups of patients: (1) Healthy volunteers, (2) Autologous HSCT recipients (who cannot develop cGVHD), and (3) Allogeneic HSCT recipients at onset of cGHVD. These analyses revealed that the urinary concentrations of DES, HP, and LP in the autologous recipients were greater or equal to the cGVHD group although both groups showed marked increase in the levels of these compounds compared to healthy individuals. These results suggest that the chemotherapy treatment has significant effects on the turnover of elastin and collagen, and that these biomarkers could be effective during prospective analyses to determine the onset of cGVHD.