Understanding mechanisms of resistance to FLT3 inhibitors in adult FLT3-mutated acute myeloid leukemia to guide treatment strategy

Critical Reviews in Oncology/Hematology, Journal Year: 2024, Volume and Issue: 201, P. 104424 - 104424

Published: June 23, 2024

The presence of FLT3 mutations, including the most common FLT3-ITD (internal tandem duplications) and FLT3-TKD (tyrosine kinase domain), is associated with an unfavorable prognosis in patients affected by acute myeloid leukemia (AML). In this setting, recent years, new inhibitors have demonstrated efficacy improving survival treatment response. Nevertheless, development primary secondary mechanisms resistance poses a significant obstacle to their efficacy. Understanding these crucial for developing novel therapeutic approaches overcome improve outcomes patients. context, use combination different targeted therapies been studied. This review provides update on molecular alterations involved inhibitors, describes how monitoring may be used guide strategy FLT3-mutated AML.

Language: Английский

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Clinical Utility and Benefits of Comprehensive Genomic Profiling in Cancer

The Journal of Applied Laboratory Medicine, Journal Year: 2024, Volume and Issue: 9(1), P. 76 - 91

Published: Jan. 1, 2024

Abstract Background Comprehensive genomic profiling (CGP) with next-generation sequencing detects genetic alterations of hundreds genes simultaneously and multiple molecular biomarkers one test. In the personalized medicine era, CGP is increasingly used for cancer diagnosis, treatment selection, prognosis prediction. Content this review, we summarize benefits CGP, clinical utility challenges setting up in laboratories. Besides identified cancer-related genes, other such as tumor mutational burden, microsatellite instability, homologous recombination deficiency are critical initiating targeted therapy. Compared conventional tests, uses less specimen shortens turnaround time if need to be tested. RNA fusion assay liquid biopsy helpful additions DNA-based by detecting fusions/splicing variants complementing tissue-based findings, respectively. Summary Many previous hurdles implementing laboratories have been gradually alleviated decrease cost, availability both open-source commercial bioinformatics tools, improved reimbursement. These changes helped make available a greater population patients improving characterization their tumors expanding eligibility trials. Additionally, results on panels could further analyzed better understand biology various cancers identify new biomarkers.

Language: Английский

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Deregulation mechanisms and therapeutic opportunities of p53-responsive microRNAs in diffuse large B-cell lymphoma

PeerJ, Journal Year: 2025, Volume and Issue: 13, P. e18661 - e18661

Published: Jan. 7, 2025

Here, we have discussed the molecular mechanisms of p53-responsive microRNAs dysregulation in response to genotoxic stress diffuse large B-cell lymphoma (DLBCL) patients. The role micro ribonucleic acids (microRNAs) p53-signaling cellular has been studied. MicroRNAs are small non-coding RNAs, which regulate genes expression at post-transcriptional level. Many them play a crucial carcinogenesis and may act as oncogenes or suppressor tumor growth. understanding effect microRNA on oncogenesis achieved recent decades opens wide opportunities for diagnosis, prediction microRNA-based cancer therapy. Development new bioinformatics tools databases supports DLBCL research. We overview studies miRNAs regulating gene associated with tumorigenesis processes, particular emphasis their growth-suppressing factors. starting point is brief description classical biogenesis pathway p53 these molecules. analyze various leading this dysregulation, including mutations TP53 gene, DNA methylation, changes host-genes copy number, genes.

Language: Английский

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Prognostication in chronic lymphocytic leukemia

Seminars in Hematology, Journal Year: 2024, Volume and Issue: 61(2), P. 83 - 90

Published: March 1, 2024

Chronic lymphocytic leukemia (CLL) is the most common type of in Western countries. CLL a highly heterogeneous disease: some patients may never require therapy and other relapse several times after different therapeutic strategies. Therefore, CLL, prognostic markers are essential to capture high-risk for clinical endpoints including early treatment requirement, progression BTK or BCL2 inhibitors Richter transformation. In stage biological biomarkers have been identified predict time requirement that could be used identify appropriate population intervention trial. However, at moment, standard care remains watch & wait since no survival benefit has trials with chemoimmunotherapy inhibitors. requiring TP53 disruptions who from long-term continuous BTKi. On opposite side spectrum, IGHV mutated devoid disruption fixed-duration venetoclax-obinutuzumab. between, heterogenous subgroup unmutated genes represents group which further efforts needed additional aimed selecting can long term BTKi therapy. context aggressive transformation namely syndrome, clonal relationship counterpart strongest biomarker. Clonally related syndrome still an unmet need requires new

Language: Английский

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Prognostic relevance of immunoglobulin heavy chain rearrangement and immunoglobulin kappa light chain rearrangement in patients with diffuse large B cell lymphoma

The Oncologist, Journal Year: 2025, Volume and Issue: 30(3)

Published: March 1, 2025

Abstract Purposes Evidence has demonstrated that monitoring of the variable, diversity, and joining gene segments (VDJ) rearrangement immunoglobulin (Ig) in circulating tumor DNA (ctDNA) is highly valuable predicting prognosis patients with diffuse large B cell lymphoma (DLBCL). In this study, we investigated role both Ig heavy chain (IGH) kappa light (IGK) rearrangements detected ctDNA samples DLBCL progression. Methods Next-generation sequencing (NGS) was used to identify dominant V(D)J clonotypic tissue 33 patients. Minimal residual disease (MRD) monitored at interim end treatment, as well follow-up time by tracking (defined “NGS MRD” method) peripheral blood (PB) samples. The nomogram established predict 12-month 24-month progression-free survival (PFS) probability. Results Prior clones identified could be retrieved tissue-matched PB 26 (78.8%, 26/33) addition IGK IGH increased MRD detection rate from 42.9% 58.0% total series. NGS imaging scans showed poor concordance treatment (Kappa = 0.24) 0.28), fair 0.46). However, confirmed improved prognostic performance compared scans, served factors for PFS treatment. Notably, predicted relapse 3 prior scans. Furthermore, found faster clone clearance rates were associated favorable prognosis. model rates, together result important predictors progression DLBCL. Conclusions via a promising noninvasive tool prediction early

Language: Английский

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Hematological Malignancies: Molecular Mechanisms and Therapy

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2438 - 2438

Published: March 9, 2025

Hematological malignancies comprise a wide range of relatively rare cancers with diverse spectrum biological and clinical presentations [...]

Language: Английский

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Analysis of 3760 hematologic malignancies reveals rare transcriptomic aberrations of driver genes

Genome Medicine, Journal Year: 2024, Volume and Issue: 16(1)

Published: May 20, 2024

Abstract Background Rare oncogenic driver events, particularly affecting the expression or splicing of genes, are suspected to substantially contribute large heterogeneity hematologic malignancies. However, their identification remains challenging. Methods To address this issue, we generated largest dataset date matched whole genome sequencing and total RNA malignancies from 3760 patients spanning 24 disease entities. Taking advantage our size, focused on discovering rare regulatory aberrations. Therefore, called outliers using an extension workflow DROP (Detection Outliers Pipeline) AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained machine learning model integrating these results prioritize new candidate disease-specific genes. Results found median seven outlier two splice-affecting per sample. Each category showed significant enrichment for already well-characterized with odds ratios exceeding three among genes in more than five samples. On held-out data, integrative modeling significantly outperformed based solely genomic data revealed promising novel Remarkably, truncated form low density lipoprotein receptor LRP1B transcript be aberrantly overexpressed about half hairy cell leukemia (HCL-V) samples and, lesser extent, closely related B-cell neoplasms. This observation, which was confirmed independent cohort, suggests as marker HCL-V subclass yet unreported functional role within Conclusions Altogether, census malignancy entities companion computational constitute unique resources deepen understanding events cancers.

Language: Английский

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Non-invasive prenatal test identifies circulating cell-free DNA chromosomal abnormalities derived from clonal hematopoiesis in aggressive hematological malignancies

Clinical and Experimental Medicine, Journal Year: 2024, Volume and Issue: 24(1)

Published: April 5, 2024

Abstract Liquid biopsy is a minimally invasive diagnostic tool for identification of tumor-related mutations in circulating cell-free DNA (cfDNA). The aim this study was to investigate feasibility, sensitivity, and specificity non-invasive prenatal test (NIPT) chromosomal abnormalities cfDNA from total 77 consecutive patients with non-Hodgkin B-cell lymphomas, Hodgkin lymphoma (HL), or plasma cell dyscrasia. In case series, half had at least one alteration, more frequently chromosome 6 (23.1%), 9 (20.5%), chromosomes 3 18 (16.7%), losses gains 7 negatively impacting on overall survival (OS), 5-year OS 26.9% median 14.6 months, respectively ( P = 0.0009 0.0004). Moreover, lymphomas the highest NIPT positivity, especially those aggressive while dyscrasia extramedullary disease higher positivity compared conventional cytogenetics analysis worse outcome. Therefore, we proposed NIPT-based liquid complementary abnormality detection hematological malignancies. However, prospective studies larger cohorts are needed validate clinical utility routinely practice.

Language: Английский

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Emerging Significance and Clinical Application of Liquid Biopsy in Early Diagnosis and Monitoring of Cancer

Journal of the Scientific Society, Journal Year: 2024, Volume and Issue: 51(2), P. 123 - 124

Published: April 1, 2024

Precision medicine in the field of cancer management continues to evolve, and so do challenges demands regarding diagnosis, prognosis, prediction treatment resistance.[1] The discovery molecular agents that can target specific genomic changes metastatic patients has revolutionized patient care.[2] tumor heterogeneity remains a daunting obstacle for clinicians who need optimize therapy regimens based on an individual's genome.[3] Tissue biopsies, which still currently represent gold standard unfortunately only reflect single point time site tumor. Such sampling method is, thus, inadequate comprehensive characterization patient's tumor, as it been demonstrated various areas within primary or metastases fact harbor different profiles.[4] Furthermore, procedure is invasive causes discomfort when opt repeat biopsy. Liquid biopsy innovative, minimally technique gained significant attention recent years its potential monitoring.[5] Unlike traditional tissue require surgical procedures obtain samples, liquid biopsies analyze circulating cells (CTCs), cell-free DNA (cfDNA), exosomes, other biomarkers body fluids such blood, urine, saliva.[6] Thus, utility provides deeper insights into biology improves care. Emerging Significance are less compared reducing risks associated with procedures. detect cancer-related mutations alterations cfDNA CTCs even at early stages, potentially before symptoms appear.[4-6] This enables earlier intervention better prognosis. allow continuous monitoring dynamics response. crucial adjusting therapeutic strategies promptly also provide more overview since they capture genetic information from multiple sites metastases, might be missed single-site biopsy.[6] minimal risk, making suitable repeated sampling. particularly beneficial tracking disease progression resistance over time. Benefits Biopsy Early Diagnosis Monitoring Cancer emerged transformative tool diagnosis cancer, leveraging noninvasive nature ability profiles fluids.[7] help cancer-specific methylation patterns stages disease. Technologies next-generation sequencing digital polymerase chain reaction used identify these high sensitivity. presence bloodstream signal existence early-stage tumor.[5-7] Advances microfluidics immunoaffinity techniques have improved isolate characterize CTCs. screen individuals risk those family history predispositions (e.g., BRCA1/2 breast cancer). proactive approach lead detection intervention.[7] For presenting nonspecific symptoms, by identifying tumor-associated epigenetic changes, diagnostic initially. By analyzing points, real-time how responding treatment. timely decisions about continuing, changing, stopping changes.[8] assessing relapse deciding additional strategies. Tumors often develop treatments. new confer resistance, allowing adjustment regimens. Continuous levels track time.[5-7] These longitudinal data valuable understanding evolution adapting plans accordingly. Quantitative analysis serve prognostic indicators. Higher poorer outcomes, guiding intensity type required. will reduce leading lower discomfort.[8] allows regular monitor captures wide range providing complete picture heterogeneity, quicker results biopsy, aiding clinical decision- making.[9] Clinical Applications being developed cancers lung, breast, colorectal, prostate cancers. Tests like fragments patterns. They actionable alterations, selection targeted therapies personalized plans.[7,8] example, epidermal growth factor receptor (EGFR) lung inform use tyrosine kinase inhibitors. burden residual measuring biomarkers, assess effectiveness make adjustments necessary.[8] enhance identification ongoing therapies, switch alternative instance, secondary EGFR gene indicate first-line Biomarkers detected through information, helping predict outcomes.[2,3] quantity correlate overall survival. helps clinician appropriate decide extent timing interventions spread. Challenges, Consideration, Future Directions represents advancement oncology, offering invasive, comprehensive, dynamic management. As research technology continue expected play increasingly central role precision medicine, transforming care, improving outcomes.[9] Despite potential, faces several challenges. Ensuring accuracy detecting low-abundance amid background normal sensitivity specificity critical, low concentrations tumor-derived materials difficult.[9,10] Developing standardized protocols sample collection, processing, necessary ensure reproducibility reliability across settings. Extensive trials validate efficacy types stages.[10] Comprehensive regulatory approvals required cost-effectiveness tests. Educating health-care providers integrating existing workflows essential widespread adoption. Its real-time, makes powerful fight against cancer.[11] technologies advance validations continue, become integral part detection, decisions, ultimately enhancing outcomes. Financial support sponsorship Nil. Conflicts interest There no conflicts interest.

Language: Английский

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The role of liquid biopsy in Neuroblastoma: A scoping review

Journal of Pediatric Surgery, Journal Year: 2024, Volume and Issue: 60(2), P. 161887 - 161887

Published: Aug. 30, 2024

Language: Английский

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