Biomedical subjects

Yasuhito Nannya

Publications and source records attributed to Yasuhito Nannya.

13 recordsLinked to original sources

PubMed2026

Late acquisition of BCR::ABL1 during clonal evolution of SAMD9-associated MDS with phenotypic shift from AML to B-ALL.

We describe a unique case of SAMD9-associated myelodysplastic syndrome (MDS) with monosomy 7 that evolved over 16 years into BCR::ABL1-positive acute myeloid leukemia (AML) and subsequently manifested as B-cell acute lymphoblastic leukemia (B-ALL). Genomic analysis at AML diagnosis revealed a germline SAMD9 mutation together with somatic RUNX1 and PPM1D mutations, supporting stepwise clonal evolution, with BCR::ABL1 emerging as a late leukemogenic event. The dominant leukemic population at AML onset showed myeloid morphology and immunophenotype, whereas a minor CD19+CD10+ population was already detectable. Following venetoclax and azacitidine therapy, the dominant leukemic phenotype shifted to B-ALL while retaining BCR::ABL1 positivity. Detection of the Philadelphia chromosome in mature neutrophils at both AML onset and ALL relapse supported multilineage involvement of a multipotent BCR::ABL1-positive clone. Ponatinib achieved disease control. This case highlights late acquisition of BCR::ABL1 during SAMD9-associated clonal evolution and therapy-driven phenotypic shift within a shared Ph-positive leukemic stem-cell hierarchy.

Humans↗

PubMed2026

BCL11B enhancer hijacking by t(14;16)(q32;q24) translocation defines a novel high-risk subtype of T-ALL.

The molecular classification of T-cell acute lymphoblastic leukemia (T-ALL) remains incomplete, limiting risk stratification and the development of targeted therapies. Enhancer hijacking is a critical oncogenic mechanism that deregulates proto-oncogenes by repositioning cisregulatory regions via structural variants. Here, we performed an integrated analysis of pediatric and adult T-ALL and mixed-phenotype acute leukemias (MPALs), using whole-genome and whole-transcriptome sequencing. This analysis identified a group of 14 patients with predominantly T-lineage neoplasms driven by a t(14;16)(q32;q24) translocation, harboring universal GATA3 mutations and CDKN2A/B deletions. Mechanistically, this translocation repositions the ThymoD locus downstream of BCL11B, causing monoallelic, ectopic overexpression of FENDRR and mesenchymal transcription factor genes FOXF1 and FOXC2 and activating epithelial-mesenchymal transition transcription signatures. Immunophenotypic and single-cell RNA sequencing analyses revealed marked lineage ambiguity with myeloid and B-cell differentiation potentials specific to this subtype. Furthermore, functional analyses in CD34+ cord blood cells demonstrated that FOXF1 overexpression promotes myeloid differentiation while suppressing T-cell differentiation, serving as a key factor for lineage specification. Clinically, this subtype was detected in 0.15% to 4.0% of T-ALL/MPAL cases depending on the cohort, showing a median age of 15 years and enrichment in adolescents and young adults. Importantly, patients with t(14;16)(q32;q24) have an extremely poor prognosis, showing a trend toward worse outcomes than high-risk groups such as KMT2A-rearranged early T-cell progenitor-like, SPI1-rearranged, and LMO2 γδ-like T-ALLs. The unique molecular landscape and poor prognosis of patients with the t(14;16)(q32;q24) translocation underscore the need for the development of novel subtype-specific therapeutic approaches.

Humans↗

PubMed2006

Genomewide screening of DNA copy number changes in chronic myelogenous leukemia with the use of high-resolution array-based comparative genomic hybridization.

Chronic myelogenous leukemia (CML) evolves from an indolent chronic phase (CP) characterized by the Philadelphia chromosome. Without effective therapy, it progresses to an accelerated phase (AP) and eventually to a fatal blast crisis (BC). To identify the genes involved in stage progression in CML, we performed a genomewide screening of DNA copy number changes in a total of 55 CML patients in different stages with the use of the high-resolution array-based comparative genomic hybridization (array CGH) technique. We constructed Human 1M arrays that contained 3,151 bacterial artificial chromosome (BAC) DNAs, allowing for an average resolution of 1.0 Mb across the entire genome. In addition to common chromosomal abnormalities, array CGH analysis unveiled a number of novel copy number changes. These alterations included losses in 2q26.2-q37.3, 5q23.1-q23.3, 5q31.2-q32, 7p21.3-p11.2, 7q31.1-q31.33, 8pter-p12(p11.2), 9p, and 22q13.1-q13.31 and gains in 3q26.2-q29, 6p22.3, 7p15.2-p14.3, 8p12, 8p21.3, 8p23.2, 8q24.13-q24.21, 9q, 19p13.2-p12, and 22q13.1-q13.32 and occurred at a higher frequency in AP and BC. Minimal copy number changes affecting even a single BAC locus were also identified. Our data suggests that at least a proportion of CML patients carry still-unknown cryptic genomic alterations that could affect a gene or genes of importance in the disease progression of CML. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Adult↗

PubMed2005

A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays.

We have developed a robust algorithm for copy number analysis of the human genome using high-density oligonucleotide microarrays containing 116,204 single-nucleotide polymorphisms. The advantages of this algorithm include the improvement of signal-to-noise (S/N) ratios and the use of an optimized reference. The raw S/N ratios were improved by accounting for the length and GC content of the PCR products using quadratic regressions. The use of constitutional DNA, when available, gives the lowest SD values (0.16 +/- 0.03) and also enables allele-based copy number detection in cancer genomes, which can unmask otherwise concealed allelic imbalances. In the absence of constitutional DNA, optimized selection of multiple normal references with the highest S/N ratios, in combination with the data regressions, dramatically improves SD values from 0.67 +/- 0.12 to 0.18 +/- 0.03. These improvements allow for highly reliable comparison of data across different experimental conditions, detection of allele-based copy number changes, and more accurate estimations of the range and magnitude of copy number aberrations. This algorithm has been implemented in a software package called Copy Number Analyzer for Affymetrix GeneChip Mapping 100K arrays (CNAG). Overall, these enhancements make CNAG a useful tool for high-resolution detection of copy number alterations which can help in the understanding of the pathogenesis of cancers and other diseases as well as in exploring the complexities of the human genome.

Algorithms↗

PubMed2005

Identification of a SRC-like tyrosine kinase gene, FRK, fused with ETV6 in a patient with acute myelogenous leukemia carrying a t(6;12)(q21;p13) translocation.

The SRC family of kinases is rarely mutated in primary human tumors. We report the identification of a SRC-like tyrosine kinase gene, FRK (Fyn-related kinase), fused with ETV6 in a patient with acute myelogenous leukemia carrying t(6;12)(q21;p13). Both reciprocal fusion transcripts, ETV6/FRK and FRK/ETV6, were expressed. In ETV6/FRK, exon 4 of ETV6 was fused in-frame to exon 3 of FRK, producing a chimeric protein consisting of the entire oligomerization domain of ETV6 and the kinase domain of FRK. The ETV6/FRK protein was shown to be constitutively autophosphorylated on its tyrosine residues. ETV6/FRK phosphorylated histones H2B and H4 in vitro to a greater extent than did FRK, suggesting it had elevated kinase activity. ETV6/FRK could transform both Ba/F3 cells and NIH3T3 cells, which depended on its kinase activity. Moreover, ETV6/FRK inhibited ETV6-mediated transcriptional repression in a dominant-negative manner. This report provides the first evidence that a SRC-like kinase gene, FRK fused with ETV6, could directly contribute to leukemogenesis by producing an oncoprotein, ETV6/FRK, with dual functions: constitutive activation of the ETV6/FRK tyrosine kinase and dominant-negative modulation of ETV6-mediated transcriptional repression.

Aged↗

PubMed2005

Chest computed tomography of late invasive aspergillosis after allogeneic hematopoietic stem cell transplantation.

Computed tomography (CT) is a powerful diagnostic tool for invasive aspergillosis (IA) after allogeneic stem cell transplantation (allo-SCT); however, little information is available concerning CT findings of late IA after allo-SCT. To characterize CT findings of late IA, we retrospectively examined medical records and high-resolution CT findings of 27 allo-SCT recipients with late IA. Either acute or chronic GVHD was diagnosed in 24 patients. All 27 patients were given corticosteroids at IA diagnosis. High-resolution CT findings included halo (n=12), centrilobular nodules (n=12), ill-defined consolidation (n=13), ground-glass attenuation (n=8), pleural effusion (n=7), pleural-based consolidation (n=4), and cavitation (n=4). CT findings showing centrilobular nodules and either halo or cavitation were classified into bronchopneumonia type and angioinvasive type, respectively. Angioinvasive-type, bronchopneumonia-type, and combination-type IA were diagnosed in 11, 8, and 4 patients, respectively. CT findings were nonspecific in the other 4 patients. One bronchopneumonia-type case and 2 angioinvasive-type IA cases were subsequently diagnosed as combination type. Although there were no significant differences in patient characteristics between the 2 types of IA, bronchopneumonia-type IA had a poorer prognosis than angioinvasive IA ( P=.022). Halo is a useful diagnostic marker in late IA as well as early IA, and late IA frequently manifests as bronchopneumonia.

Adrenal Cortex Hormones↗

PubMed2004

Incidence of invasive aspergillosis after allogeneic hematopoietic stem cell transplantation with a reduced-intensity regimen compared with transplantation with a conventional regimen.

To evaluate the clinical characteristics of invasive aspergillosis (IA) after reduced-intensity stem cell transplantation (RIST) compared with those after conventional stem cell transplantation (CST), we examined the medical records of 486 CST and 178 RIST recipients. The overall incidence of IA after allogeneic transplantation was 35 (5.3%) of 664, which gave a 3-year cumulative incidence of 5.6%. The estimated 3-year incidence of IA in CST and RIST was 4.5% and 8.2% (P = .045), respectively, but the mortality rates were similar (76% and 86%). The median onset of IA after RIST (day 127) occurred significantly later than that after CST (day 97). A multivariate analysis revealed that IA was associated with age older than 50 years (relative risk, 2.12; 95% confidence interval, 1.08-4.17; P = .03) and the presence of acute and/or chronic GVHD (relative risk, 6.2; 95% confidence interval, 2.4-16.4; P = .0002). IA remains an important complication after allogeneic transplantation, regardless of the type of conditioning regimen.

Adolescent↗

PubMed2004

Clinical significance of peripheral blood erythroblastosis after hematopoietic stem cell transplantation.

Erythroblasts (EBL) are normally not observed in peripheral blood, but may be found in patients suffering from a variety of severe diseases. The detection of EBL in peripheral blood has been shown to be associated with a poor prognosis. However, the clinical significance of peripheral erythroblastosis after hematopoietic stem cell transplantation (HSCT) has not been evaluated. We retrospectively analyzed the records of 161 patients who underwent HSCT at our hospital from June 1995 to October 2001. EBL at any level were detected in 94% of the patients. Forty-four and 11 patients experienced erythroblastosis exceeding 200 and 1,000/ul, respectively. The erythroblast count was higher in patients who died than in the survivors (geometric mean value 184 vs. 100/ul, P=0.01). High-level erythroblastosis ( >1,000/ul) within 180 days after HSCT was associated with an extremely poor prognosis (median survival 22.5 days). Among the possible confounding factors, the use of total body irradiation (RR 2.35, 95% CI 1.22 - 4.54, P=0.011) and the disease status before transplantation (RR 2.51, 95% CI 1.15 - 5.49, P=0.021) were independent significant factors for erythroblastosis after HSCT. As for post-transplant events, a high EBL concentration was frequently preceded by graft-vs.-host disease, thrombotic microangiopathy, hypoxia, and hematological relapse.

Adult↗

PubMed2004

Prospective comparison of the diagnostic potential of real-time PCR, double-sandwich enzyme-linked immunosorbent assay for galactomannan, and a (1-->3)-beta-D-glucan test in weekly screening for invasive aspergillosis in patients with hematological disorders.

The establishment of an optimal noninvasive method for diagnosing invasive aspergillosis (IA) is needed to improve the management of this life-threatening infection in patients with hematological disorders, and a number of noninvasive tests for IA that target different fungal components, including galactomannan, (1-->3)-beta-d-glucan (BDG), and Aspergillus DNA, have been developed. In this study, we prospectively evaluated the diagnostic potential of three noninvasive tests for IA that were used in a weekly screening strategy: the double-sandwich enzyme-linked immunosorbent assay (ELISA) for galactomannan (Platelia Aspergillus), a real-time PCR assay for Aspergillus DNA (GeniQ-Asper), and an assay for BDG (beta-glucan Wako). We analyzed 149 consecutive treatment episodes in 96 patients with hematological disorders who were at high risk for IA and diagnosed 9 proven IA cases, 2 probable IA cases, and 13 possible invasive fugal infections. In a receiver-operating characteristic (ROC) analysis, the area under the ROC curve was greatest for ELISA, using two consecutive positive results (0.97; P = 0.036 for ELISA versus PCR, P = 0.055 for ELISA versus BDG). Based on the ROC curve, the cutoff for the ELISA could be reduced to an optical density index (O.D.I.) of 0.6. With the use of this cutoff for ELISA and cutoffs for PCR and BDG that give a comparable level of specificity, the sensitivity/specificity/positive predictive value/negative predictive value of the ELISA and the PCR and BDG tests were 1.00/0.93/0.55/1.00, 0.55/0.93/0.40/0.96, and 0.55/0.93/0.40/0.96, respectively. In conclusion, among these weekly screening tests for IA, the double-sandwich ELISA test was the most sensitive at predicting the diagnosis of IA in high-risk patients with hematological disorders, using a reduced cutoff of 0.6 O.D.I.

Adolescent↗

PubMed2003

Rapid diagnosis of invasive pulmonary aspergillosis by quantitative polymerase chain reaction using bronchial lavage fluid.

Polymerase chain reaction (PCR) is a sensitive method for detection of Aspergillus DNA in bronchoalveolar lavage fluid, but it has not yet been able to distinguish infection from contamination. We have established a technique to quantify Aspergillus DNA using a real-time PCR method to resolve this problem, and we report herein a successful application of real-time PCR to diagnose invasive pulmonary aspergillosis by comparing the amount of Aspergillus DNA in bronchial lavage fluid from an affected area to that from an unaffected area. This novel tool will provide rapid, sensitive, and specific diagnosis of pulmonary aspergillosis.

Adult↗

PubMed2003

Reduced-intensity bone marrow transplantation from an alternative unrelated donor for myelodysplastic syndrome of first-donor origin.

A male patient had a relapse of myelodysplastic syndrome (MDS) 2 years after BMT from a female matched unrelated donor. Conventional cytogenetics, FISH, and short-tandem repeat chimerism analysis proved a relapse of donor origin. He underwent reduced-intensity BMT after a conditioning with fludarabine and busulfan, since he had impaired renal, liver, and pulmonary functions. Chimerism analysis on day 28 after the second BMT showed mixed chimerism of the first and the second donors, which later turned to full second-donor chimerism on day 60. He developed grade II acute GVHD of the skin and cytomegalovirus reactivation, but both were improved with methylprednisolone and ganciclovir, respectively. He remains in complete remission 6 months after the second BMT. Reduced-intensity second BMT from an alternative donor appeared to be a tolerable treatment option for donor-derived leukemia/MDS after the first conventional transplantation.

Adult↗

PubMed2003

Molecular cytogenetic analyses of HIG, a novel human cell line carrying t(1;3)(p36.3;q25.3) established from a patient with chronic myelogenous leukemia in blastic crisis.

Chromosomal abnormalities involving 1p36, 3q21, and/or 3q26 have been reported in a subset of myeloid neoplasms having characteristic dysmegakaryopoiesis, and the overexpression of EVI1 on 3q26 or of MEL1 on 1p36 has been implicated in their pathogenesis. We describe molecular cytogenetic analyses of a novel human cell line, HIG, established from a unique case in which a novel translocation t(1;3)(p36;q26) appeared as the sole additional chromosomal abnormality at the time of blastic transformation of chronic myelogenous leukemia. The patient displayed clinical features resembling those of the 3q21q26 syndrome. The HIG cell line retained der(1)t(1;3)(p36;q26) but lost t(9;22)(q34;q11). To identify the relevant gene that would be deregulated by this translocation, we molecularly cloned the translocation's breakpoints. They were distant from the breakpoint cluster regions of the 3q21q26 syndrome or t(1;3)(p36;q21), and neither the EVI1 nor the MEL1 transcript was detected in the HIG cell line. None of the genes located within 150 kilobase pairs of the breakpoints were aberrantly expressed, suggesting that in this case other gene(s) more distant from the breakpoints are deregulated by possible remote effects. Further analyses of the deregulated genes in the HIG cell line should provide important insight into the mechanisms involved in these types of leukemias.

Blast Crisis↗

PubMed2002

Prognostic factors in elderly patients with acute myelogenous leukemia: a single center study in Japan.

We retrospectively analyzed data of 47 patients aged 60 years or older, hospitalized in our institution with the diagnosis of acute myelogenous leukemia (AML), and searched for prognostic factors. Induction with anthracyclines significantly correlated with better complete remission (CR) rate (P = 0.0016) and overall survival (OS) (P < 0.001). Another factor significantly affecting CR rate was higher age (> 70 years) (P = 0.042). Therapy-non-related factors predictive for shorter OS in univariate analyses were age older than 70 years (P = 0.003), percentage of blasts in bone marrow more than 80% (P = 0.048), serum lactate dehydrogenase level higher than 250 U l(-1) (P = 0.032). In stepwise cox proportional hazard regression model, all the four factors predictive for poor OS remained to be independently and significantly prognostic for shorter OS. Only two patients receiving anthracyclines died within 30 days and the frequency was not different from that in patients not receiving anthracyclines. The use of anthracyclines as induction therapy is recommended even in the elderly patients.

Age Factors↗