Advances in Molecular Pathology, Journal Year: 2024, Volume and Issue: 7(1), P. 53 - 61
Published: July 20, 2024
Language: Английский
Genes Chromosomes and Cancer, Journal Year: 2025, Volume and Issue: 64(1)
Published: Jan. 1, 2025
ABSTRACT Myelodysplastic neoplasia with complex karyotype (CK‐MDS) poses significant clinical challenges and is associated poor survival. Detection of structural variants (SVs) crucial for diagnosis, prognostication, treatment decision‐making in MDS. However, the current standard‐of‐care (SOC) cytogenetic testing, relying on karyotyping, often yields ambiguous results cases CK. Here, SV detection by novel optical genome mapping (OGM) technique was explored 15 CK‐MDS cases, which collectively harbored 85 chromosomes abnormalities reported SOC. Additionally, OGM utilized discovery SVs. Altogether, detected corresponding > 5 Mbp alterations 73 out SOC abnormalities, resulting an 86% concordance rate. provided further specification these revealing that 64% altered were affected multiple SVs or chromoanagenesis. Prominently, only 5% missing true monosomies. In addition, not as abnormal karyotyping 93% clinically relevant gene‐level information, such TP53 , MECOM NUP98 IKZF1 ETV6 . Analysis revealed two previously unreported gene‐fusions ( SCFD1::ZNF592 VPS8::LRBA ), both confirmed transcriptome sequencing. Furthermore, repositioning CCDC26 (8q24.21) identified a potential cause inappropriate gene activation affecting SOX7 respectively. This study shows can significantly enhance diagnostic analysis highlights utility identifying cancer genomes.
Language: Английский
Citations
1
Cancer Cell International, Journal Year: 2024, Volume and Issue: 24(1)
Published: May 19, 2024
Abstract Introduction Acute myeloid leukemia (AML) is a complex hematologic malignancy characterized by uncontrolled proliferation of precursor cells within bone marrow. Despite advances in understanding its molecular underpinnings, AML remains therapeutic challenge due to high relapse rate and clonal evolution. Methods In this retrospective study, we analyzed data from 24 patients diagnosed at single institution between January 2017 August 2023. Comprehensive genetic analyses, including chromosomal karyotyping, next-generation sequencing, gene fusion assays, were performed on marrow samples obtained initial diagnosis relapse. Clinical data, treatment regimens, patient outcomes also documented. Results Mutations core genes FLT3 , NPM1 DNMT3A IDH2 frequently discovered diagnostic sample remained sample. -ITD, TP53 KIT RUNX1 WT1 mutation acquired one each. Gene assays revealed stable patterns, while karyotype analyses indicated greater diversity mutations relapsed patients. Clonal evolution patterns varied, with some cases showing linear or branching others exhibiting no substantial change Conclusions Our study integrates karyotype, rearrangements, results provide further heterogeneity We demonstrate the clinical relevance specific emphasizing need for personalized therapies measurable residual disease monitoring management. By bridging gap genetics outcome, move closer tailored improved prognoses.
Language: Английский
Citations
7
HemaSphere, Journal Year: 2024, Volume and Issue: 8(9)
Published: Sept. 1, 2024
Abstract Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a heterogeneous molecular landscape. In the pediatric context, NUP98 gene frequent target of chromosomal rearrangements that are linked to poor prognosis and unfavorable treatment outcomes in different AML subtypes. The translocations fuse diverse array partner genes, resulting fusion proteins novel functions. oncoproteins induce aberrant biomolecular condensation, abnormal expression programs, re‐wired protein interactions which ultimately cause alterations cell cycle changes cellular structures, all contribute development. extent these effects steered by functional domains partners influence concomitant somatic mutations. this review, we discuss complex characteristics potential therapeutic approaches for fusion‐driven AML.
Language: Английский
Citations
5
Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(20)
Published: Oct. 14, 2024
As epigenetic therapies continue to gain ground as potential treatment strategies for cancer and other diseases, compounds that target histone lysine methylation the enzyme complexes represent a major frontier therapeutic development. Clinically viable targeting activities of methyltransferases (HKMT) demethylases (HKDMs) have only recently begun emerge following FDA approval EZH2 inhibitor tazemetostat in 2020 remain limited well-studied SET domain-containing HKMTs their opposing HKDMs. These include H3K27 EZH2/EZH1, singular H3K79 methyltransferase DOT1L, H3K4 MLL1/COMPASS well H3K9 H3K36 methyltransferases. They additionally H3K4/9-preferential demethylase LSD1 H3K4-, H3K27-, H3K36-preferential KDM5, KDM6, KDM2 subfamilies, respectively. This Review discusses results recent clinical preclinical studies relevant all these existing therapies. It provides an update on advancements development, more basic molecular understanding, within past 5 years approximately. also offers perspective departs from long-predominant "histone code" metaphor, emphasizing complex-disrupting inhibitors proximity-based approaches rather than catalytic domain outlook future
Language: Английский
Citations
5
Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)
Published: March 6, 2025
The histone H3K36-specific methyltransferase ASH1L plays a critical role in development and is frequently dysregulated human diseases, particularly cancer. Here, we report on the biological functions of C-terminal region encompassing bromodomain (ASH1LBD), plant homeodomain (ASH1LPHD) finger, bromo-adjacent homology (ASH1LBAH) domain, structurally characterize these domains, describe their mechanisms action, explore functional crosstalk between them. We find that ASH1LPHD recognizes H3K4me2/3, whereas neighboring ASH1LBD ASH1LBAH have DNA binding activities. function driving force for association with linker nucleosome, large interface stabilizes fold, merging two domains into single module. show involved embryonic stem cell differentiation co-localizes H3K4me3 but not H3K36me2 at transcription start sites target genes genome wide, interaction inhibitory to H3K36me2-specific catalytic activity ASH1L. Our findings shed light mechanistic details by which associate chromatin regulate enzymatic
Language: Английский
Citations
0
Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14
Published: Sept. 5, 2024
This is the first report of NUP98::LEDGF positive malignant hematological tumor expressing T cell and myeloid lineage antigens. Patients carrying this fusion gene have a high relapse rate poor prognosis, allo-HSCT may be an option to cure disease. patient underwent allo-HSCT, occurred three months post-transplantation. Subsequent screening at our hospital confirmed presence gene, salvage therapy was administered, followed by successful second allo-HSCT. Furthermore, we included eight previously reported cases from literature for analysis discuss.
Language: Английский
Citations
2
Life, Journal Year: 2024, Volume and Issue: 14(3), P. 309 - 309
Published: Feb. 27, 2024
Secondary acute myeloid leukemia (sAML) is a heterogeneous malignant hematopoietic disease that arises either from an antecedent hematologic disorder (AHD) including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), aplastic anemia (AA), or as result of exposure to genotoxic chemotherapeutic agents radiotherapy (therapy related AML, tAML). sAML diagnosed when the number blasts ≥20% in bone marrow peripheral blood, and it characterized by poor prognosis, resistance therapy low overall survival rate. With recent advances next generation sequencing technologies, our understanding molecular events associated with evolution has significantly increased opened new perspectives for development novel therapies. The genetic aberrations are affect genes involved processes such splicing, chromatin modification genome integrity. Moreover, non-coding RNAs’ emerged important contributing factor leukemogenesis. For decades, standard treatment secondary AML been 7 + 3 regimen cytarabine daunorubicin which prolongs several months, but modifications dosage delivery extended time. Apart traditional chemotherapy, stem cell transplantation, CAR-T small molecule inhibitors have also treat sAML.
Language: Английский
Citations
2
Cancers, Journal Year: 2023, Volume and Issue: 15(21), P. 5233 - 5233
Published: Oct. 31, 2023
Neuroblastoma is the most common extracranial solid tumour in children, accounting for 15% of paediatric cancer deaths. Multiple genetic abnormalities have been identified as prognostically significant neuroblastoma patients. Optical genome mapping (OGM) a novel cytogenetic technique used to detect structural variants, which has not previously tested neuroblastoma. We OGM identify copy number and variants (SVs) may missed by standard techniques.Five cell lines (SH-SY5Y, NBLW, GI-ME-N, NB1691 SK-N-BE2(C)) two tumours were analysed using with Bionano Saphyr® instrument. The results Access software compared previous analyses including G-band karyotyping, FISH (fluorescent situ hybridisation), single-nucleotide polymorphism (SNP) array RNA fusion panels lines, SNP arrays whole sequencing (WGS) tumours.OGM detected found methods provided estimates absolute numbers amplified genes. SVs, genes potential clinical significance.OGM can reliably clinically variations single test. prove be more time- cost-effective than current techniques
Language: Английский
Citations
2
Cancers, Journal Year: 2024, Volume and Issue: 16(2), P. 418 - 418
Published: Jan. 18, 2024
Acute leukemia is a particularly problematic collection of hematological cancers, and, while somewhat rare, the survival rate patients typically abysmal without bone marrow transplantation. Furthermore, traditional chemotherapies used as standard-of-care for cause significant side effects. Understanding evolution to identify novel targets therefore, drug treatment regimens medical need. Genomic rearrangements and other structural variations (SVs) have long been known be causative pathogenic in multiple types cancer, including leukemia. These SVs may involved cancer initiation, progression, clonal evolution, resistance, better understanding from individual help guide therapeutic options. Here, we show utilization optical genome mapping (OGM) detect samples with Importantly, this technology provides an unprecedented level granularity quantitation unavailable current techniques allows unbiased detection SVs, which relevant disease pathogenesis and/or resistance. Coupled chemosensitivities these FDA-approved oncology drugs, how impartial integrative analysis diverse datasets can associate detected genomic sensitivity profiles. Indeed, insertion gene MUSK shown associated increased clinically agent Idarubicin, partial tandem duplication events KMT2A are related efficacy another frontline treatment, Cytarabine.
Language: Английский
Citations
0
Advances in Molecular Pathology, Journal Year: 2024, Volume and Issue: 7(1), P. 53 - 61
Published: July 20, 2024
Language: Английский
Citations
0