ABSTRACT
We present a leukemia case that exhibits a chromosomal translocation t(11;16)(q23;q23), which results in the expression of a novel KMT2A fusion gene. This novel fusion, KMT2A-USP10, was found in a relapse of acute myeloid leukaemia M5a. USP10 belongs to a protein family that deubiquitinates a distinct set of target proteins, and thus, increases the steady state protein levels of its target subproteome. One of the USP10 targets is TP53. Wildtype TP53 is usually rescued from proteasomal degradation by USP10. As most KMT2A leukemias display wildtype p53 alleles, one might argue that the disruption of an USP10 allele can be classified as a pro-oncogenic event.
Subject(s)
Histone-Lysine N-Methyltransferase/genetics , Leukemia, Myeloid, Acute/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Translocation, Genetic/genetics , Ubiquitin Thiolesterase/genetics , Adolescent , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 16/genetics , Humans , Karyotyping , Leukemia, Myeloid, Acute/pathology , Male , Oncogene Proteins, Fusion/genetics , Tumor Suppressor Protein p53/geneticsABSTRACT
T(16;21)(p11;q22)/FUS-ERG is a rare but recurrent translocation in acute leukemias and in some types of solid tumors. Due to multiple types of FUS-ERG transcripts, PCR-based minimal residual disease detection is impeded. In this study, we evaluated a cohort of pediatric patients with t(16;21)(p11;q22)/FUS-ERG and revealed fusion gene breakpoints. We implemented next-generation sequencing (NGS) on long PCR amplicons for the detection of fusion genes with unknown partners or DNA breakpoints. That allowed us to describe different fusion variants of FUS/ERG in different patients and to detect MRD on both RNA and DNA levels. We also found several accompanying mutations in epigenetic regulators (DNMT3A, ASXL1, BCOR) by targeted NGS approach in AML cases. These mutations preceded full transformation by t(16;21)(p11;q22)/FUS-ERG and allowed us to trace clonal evolution on all steps of therapy. As a casual observation, the ASXL1 mutation was found in the unrelated donor hematopoietic cells.
Subject(s)
Chromosomes, Human, Pair 16 , Chromosomes, Human, Pair 21 , Leukemia, Myeloid, Acute/genetics , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , RNA-Binding Protein FUS/genetics , Translocation, Genetic , Amino Acid Substitution , Child, Preschool , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 22 , Cohort Studies , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methyltransferase 3A , DNA Mutational Analysis , Female , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/prevention & control , Leukemia, Myeloid, Acute/therapy , Male , Mutation , Neoplasm Recurrence, Local/prevention & control , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/prevention & control , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Tumor BurdenABSTRACT
INTRODUCTION: Accurate detection of GATA1 mutation is highly significant in patients with acute myeloid leukemia (AML) and trisomy 21 as it allows optimization of clinical protocol. This study was aimed at (a) enhanced search for GATA1 mutations; and (b) characterization of molecular landscapes for such conditions. METHODS: The DNA samples from 44 patients with newly diagnosed de novo AML with trisomy 21 were examined by fragment analysis and Sanger sequencing of the GATA1 exon 2, complemented by targeted high-throughput sequencing (HTS). RESULTS: Acquired GATA1 mutations were identified in 43 cases (98%). Additional mutations in the genes of JAK/STAT signaling, cohesin complex, and RAS pathway activation were revealed by HTS in 48%, 36%, and 16% of the cases, respectively. CONCLUSIONS: The GATA1 mutations were reliably determined by fragment analysis and/or Sanger sequencing in a single PCR amplicon manner. For patients with extremely low blast counts and/or rare variants, the rapid screening with simple molecular approaches must be complemented with HTS. The JAK/STAT and RAS pathway-activating mutations may represent an extra option of targeted therapy with kinase inhibitors.
Subject(s)
Down Syndrome/genetics , GATA1 Transcription Factor/genetics , Leukemia, Myeloid, Acute/genetics , Child , Down Syndrome/complications , Exons , Female , Humans , Leukemia, Myeloid, Acute/complications , Male , MutationABSTRACT
The increasing use of the integrase strand transfer inhibitor (INSTI) class for the treatment of HIV-infection has pointed to the importance of analyzing the features of HIV-1 subtypes for an improved understanding of viral genetic variability in the occurrence of drug resistance (DR). In this study, we have described the prevalence of INSTI DR in a Russian cohort and the genetic features of HIV-1 integrase sub-subtype A6. We included 408 HIV infected patients who were not exposed to INSTI. Drug resistance mutations (DRMs) were detected among 1.3% of ART-naïve patients and among 2.7% of INSTI-naïve patients. The prevalence of 12 polymorphic mutations was significantly different between sub-subtypes A6 and A1. Analysis of the genetic barriers determined two positions in which subtype A (A1 and A6) showed a higher genetic barrier (G140C and V151I) compared with subtype B, and one position in which subtypes A1 and B displayed a higher genetic barrier (L74M and L74I) than sub-subtype A6. Additionally, we confirmed that the L74I mutation was selected at the early stage of the epidemic and subsequently spread as a founder effect in Russia. Our data have added to the overall understanding of the genetic features of sub-subtype A6 in the context of drug resistance.
Subject(s)
Drug Resistance, Viral/genetics , HIV Integrase Inhibitors/pharmacology , HIV Integrase/genetics , HIV-1/drug effects , Adult , Female , Genotype , HIV Infections/drug therapy , HIV Infections/epidemiology , HIV Integrase/classification , HIV-1/enzymology , Humans , Male , Mutation , Phylogeny , Polymorphism, Genetic , Prevalence , Russia , Sequence Analysis, DNAABSTRACT
Although HIV-1 subtype A has predominated in Russia since the end of the 20th century, other viral variants also circulate in this country. The dramatic outbreak of HIV-1 subtype G in 1988-1990 represents the origin of this variant spreading in Russia. However, full genome sequencing of the nosocomial viral variant and an analysis of the current circulating variants have not been conducted. We performed near full-length genome sequencing and phylogenetic and recombination analyses of 11 samples; the samples were determined to be subtype G based on an analysis of the pol region. Three samples were reliably obtained from patients infected during the nosocomial outbreak. The other 8 samples were obtained from patients who were diagnosed in 2010-2015. Phylogenetic analysis confirmed that a man from the Democratic Republic of the Congo was the origin of the outbreak. We also found that currently circulating viral variants that were genotyped as subtype G according to their pol region are in fact unique recombinant forms. These recombinant forms are similar to the BG-recombinants from Western Europe, particularly Spain and Portugal. The limitations of subtyping based on the pol region suggest that these viral variants are more widespread in Europe than is currently supposed.
Subject(s)
Genotype , HIV Infections/epidemiology , HIV-1/classification , HIV-1/genetics , Disease Transmission, Infectious , HIV Infections/transmission , HIV Infections/virology , HIV-1/isolation & purification , Humans , Male , Molecular Epidemiology , Phylogeny , Russia/epidemiology , Sequence Analysis, DNA , Whole Genome SequencingABSTRACT
The prevalence of HIV infection in different Russian regions is nonuniform. In the Tomsk region (TR), 2020 HIV new infection cases were recorded in 2013, the morbidity having increased 5.9-fold as compared to 2012. In total, 64 blood plasma samples from primary HIV cases have been examined. HIV-specific fragments of the pol gene have been obtained for 61 samples (of protease for 58 and of integrase for 23) and of the env gene V3 region for 40 samples. Phylogenetic analysis of the determined HIV-1 sequences has detected CRF63_02A1 in 55 (90.2%) cases, whereas HIV subtype A1, characteristic of Russia, has been observed in only three (4.9%) patients. Three (4.9%) cases contain CRF63_02A1/A recombinant variants. This article demonstrates that a drastic activation of the epidemic in the Tomsk region is accompanied by a rapid spreading of the recently described HIV-1 CRF63_02A1, which we detected in the Novosibirsk region outbreak of 2008.
Subject(s)
Genotype , HIV Infections/epidemiology , HIV Infections/virology , HIV-1/classification , HIV-1/genetics , Adolescent , Adult , Cluster Analysis , Female , HIV-1/isolation & purification , Humans , Male , Middle Aged , Molecular Epidemiology , Molecular Sequence Data , Phylogeny , Russia/epidemiology , Sequence Analysis, DNA , Sequence Homology , Young AdultABSTRACT
One of the factors determining a high degree of heterogeneity in the HIV population is recombination-based variation, which leads to the emergence of the virus variants with a mosaic genome. An example is CRF63_02A1, an HIV-1 variant currently spreading in the Siberian region of Russia. To prove that this HIV-1 variant is a new circulating recombinant form that had emerged as a result of repeated recombination between CRF02_AG and subtype A, we have isolated seven full-length HIV genomes and theoretically analyzed them, that is, reconstructed the phylogenetic relationships, determined recombination breakpoints and regions, and compared them with the regions known for CRF02_AG.