Search

The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear, and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA) (15 to 39 years old, n = 193) and adults (40 to 64 years old, n = 161) with Philadelphia chromosome-negative (Ph−) B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with 2 novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2 and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1 R132C or IDH2 R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified 2 novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL. more...

The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear, and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA) (15 to 39 years old, n = 193) and adults (40 to 64 years old, n = 161) with Philadelphia chromosome-negative (Ph−) B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with 2 novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1R132C or IDH2R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified 2 novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL. more...

Prevalent photosensitizing agents for photodynamic therapy (PDT) suffer from their relatively large molecular weights causing photodermatosis. In this regard, low molecular weight pyrene could be an efficient photosensitizer except for its extreme hydrophobicity. To tackle the insolubility of pyrene, we synthesized 1-carboxypyren-2-yl C-glucoside 4by a tethered C-glucosylation and 1-pyrenylmethyl O-glucoside 5by a simple O-glucosylation. Compounds 4and 5showed modest water solubilities of 72 and 47 μg/mL, respectively. Whereas compound 4partially underwent a cyclization reaction at pH 3 to give the corresponding δ-valerolactone 15bin 31% yield after 24 h, it is stable at pH 5–9 for at least a week. The 1O2-producing photosensitizabilities of 4and 5were sufficient to apply to PDT. Although compound 5was uptaken by HeLa cells and showed a good PDT activity, compound 4showed neither a sufficient cell uptake nor PDT effect. The binding modes of compounds 4and 5to concanavalin A were specific and unspecific, respectively. These results demonstrate that compounds 4and 5are within a pharmacologically acceptable range as oral drugs and could be a fluorescence imaging probe for α-glucose/mannose receptors and a photosensitizing agent for PDT, respectively. more...

Ribosomes polymerize nascent peptides through repeated inter-subunit rearrangements between the classic and hybrid states. The peptidyl-tRNA, the intermediate species during translation elongation, stabilizes the translating ribosome to ensure robust continuity of elongation. However, the translation of acidic residue-rich sequences destabilizes the ribosome, leading to a stochastic premature translation cessation termed intrinsic ribosome destabilization (IRD), which is still ill-defined. Here, we dissect the molecular mechanisms underlying IRD in Escherichia coli. Reconstitution of the IRD event reveals that (1) the prolonged ribosome stalling enhances IRD-mediated translation discontinuation, (2) IRD depends on temperature, (3) the destabilized 70S ribosome complex is not necessarily split, and (4) the destabilized ribosome is subjected to peptidyl-tRNA hydrolase-mediated hydrolysis of the peptidyl-tRNA without subunit splitting or recycling factors-mediated subunit splitting. Collectively, our data indicate that the translation of acidic-rich sequences alters the conformation of the 70S ribosome to an aberrant state that allows the noncanonical premature termination. more...

Background: Recent sequencing analyses have identified distinct genetic subtypes of diffuse large B-cell lymphoma (DLBCL). The MCD subtype, characterized by MYD88L265P and CD79Bgene mutations, is frequently found in DLBCL that progresses to the central nervous system (CNS), known as secondary CNS lymphoma (sCNSL) (Ollila, Blood 2021). In addition, the MCD subtype is also frequently found in primary CNS lymphoma (PCNSL) (Radke, Nat commun 2022). Therefore, we hypothesized that specific genetic alterations that are present in the initial DLBCL tumors are associated with their progression to the CNS. We aimed to investigate i) the clinical impact of genetic subtypes of DLBCL and ii) genomic mutations that may be associated with sCNSL. To this end, genetic alterations in DLBCL samples at diagnosis that later developed into sCNSL were evaluated using whole-exome sequencing (WES). more...

Mitochondria contain the translocator of the outer mitochondrial membrane (TOM) for protein entry into the organelle, and its subunit Tom40 forms a protein-conducting channel. Here we report the role of Tom40 in protein translocation across the membrane. The site-specific photocrosslinking experiment revealed that translocating unfolded or loosely folded precursor segments of up to 90 residues can be associated with Tom40. Purified Tom40 bound to non-native proteins and suppressed their aggregation when they are prone to aggregate. A denatured protein bound to the Tom40 channel blocked the protein import into mitochondria. These results indicate that, in contrast to the nonstick tunnel of the ribosome for polypeptide exit, the Tom40 channel offers an optimized environment to translocating non-native precursor proteins by preventing their aggregation. more...

In order to develop fluorescent guanine analogs having substitutions at the 7-positions, 7-(benzofuran-2-yl)-7-deazahypoxanthine (1a) and 7-(benzofuran-2-yl)-7-deazaguanine (1b), were synthesized from 7-deaza-7-iodohypoxanthine and 7-deaza-7-iodo-2-N-pivaloylguanine via a Suzuki–Miyaura cross-coupling, respectively. Compound 1bshowed strong fluorescence, with higher fluorescent quantum yields in less polar solvents; meanwhile, 1ashowed higher activity in more polar solvents. It is expected that the guanine analogs can be incorporated into nucleosides to develop new fluorescent oligonucleotides. more...

Immunoglobulin (Ig)/T-cell receptor (TCR) gene rearrangement-based molecular minimum residual disease (MRD) monitoring has become one of the most powerful prognostic indicators for patients with acute lymphoblastic leukemia (ALL). Infant ALL has a poor prognosis and requires therapeutic development based on accurate MRD assessment. However, there are some difficulties associated with the highly sensitive detection of MRD based on Ig/TCR gene rearrangements in infant ALL cases, compared to other B-ALL cases, because of the immature Ig/TCR gene rearrangement patterns and their oligoclonality. Since KMT2A(MLL) gene rearrangements are identified in infant ALL at a high frequency, the use of KMT2A rearranged sequences is an alternative method for MRD detection in KMT2A rearranged ALL cases. However, identifying the genomic breakpoints in KMT2A rearrangements by conventional methods is laborious and difficult in routine practice. To detect molecular MRD markers in infant ALL cases, we designed capture probes covering the coding and recognition signal sequences of the V, D, and J genes of the Ig/TCR loci and common genomic breakpoints in KMT2A, AFF1 (AF4), MLLT3 (AF9), MLLT1 (ENL), MLLT10 (AF10), and ELL. 88 infant ALL cases from the JPLSG MLL-10 study, including 73 cases with KMT2A rearrangements, were analyzed by high-throughput target-capture sequencing on the Illumina platform. The sequenced data were analyzed with the Ig/TCR recombination analysis tool Vidjil and the Genomon pipeline for detection of KMT2A rearrangements. more...

No relevant conflicts of interest to declare.

We developed a new artificial DNA triplex triad which has the adenine nucleobase in the first strand. This triplex triad (A-;0"">-C*) is composed of adenine, pseudouridine and 5-sudstituted cytosine as the 1st, 2nd and 3rd strand nucleobases, respectively. The molecular design and synthesis of the nucleobases for the 2nd and 3rd strand of the triplex are also described. more...

In this paper, we reported our attempt to use a 5arylcytosine (dCar) and the abasic site (φ) as an artificial base pair for DNA triplex. The idea was confirmed by the molecular modeling studied in which the aromatic group of ph which protrudes in the major groove was buried into the cleft formed by the φ residue in the TFO. We synthesized three kinds of dCar and the oligonucleotides incorporating them. Our UV-melting experiments revealed that the DNA triplex containing the dCph▪φ was more stable than that containing dC▪φ pair. Moreover, the dCph▪φ pair was more stable than any other dCph▪Y pairs such as dCph▪G, dCph▪C, dCph▪T and dCph▪A. These results indicated the possibility that the appropriate pair of dCAr and φ could be the new sequence code of DNA triplex. We also carried out the Tm analyses of other TFOs incorporating dCAr and φ, and clarified the stability of these triplexes. more...

The application of oxidatively cleavable tritylsulfenyl (TrS) group to the synthesis of branched DNA is described. The TrS protecting group can be removed by treatment with 1 M aqueous iodine, while it is stable toward an oxaziridine‐type oxidant. At the same time, the sulfur‐oxygen linkage showed sufficient stability under the acidic and basic conditions used in oligonucleotide synthesis. These properties of the TrS group enabled the synthesis of branched DNA using a branched phosphoramidite in which the two hydroxy groups are protected by a 4,4′‐dimethoxytrityl (DMTr) group or a TrS group. In this unit, we describe an example of the synthesis of a three‐way branched DNA using a branched phosphoramidite. Curr. Protoc. Nucleic Acid Chem. 58:2.18.1‐2.18.19. © 2014 by John Wiley & Sons, Inc. more...