Search Results (123)

Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic malignancy defined by the uncontrolled proliferation of lymphoid precursors. Accurate diagnosis and effective therapeutic strategies hinge on a comprehensive understanding of the genetic and molecular landscape of ALL. This review synthesizes the latest updates in cytogenetic and molecular classifications, emphasizing the 2022 World Health Organization (WHO) and International Consensus Classification (ICC) revisions. Key chromosomal alterations such as BCR::ABL1 and ETV6::RUNX1 and emerging subtypes including Ph-like ALL, DUX4, and MEF2D rearrangements are examined for their prognostic significance. Furthermore, we assess novel diagnostic tools, notably next-generation sequencing (NGS) and optical genome mapping (OGM). While NGS excels at identifying point mutations and small indels, OGM offers high-resolution structural variant detection with 100% sensitivity in multiple validation studies. These advancements enhance our grasp of leukemogenesis and pave the way for precision medicine in both B- and T-cell ALL. Ultimately, integrating these innovations into routine diagnostics is crucial for personalized patient management and improving clinical outcomes. Full article

To deliver the most effective cancer treatment, clinicians require rapid and accurate diagnoses that delineate tumor type, stage, and prognosis. Consequently, minimizing the need for repetitive and invasive procedures like biopsies and myelograms, along with their associated risks, is a critical challenge. Non-invasive monitoring offers a promising avenue for tumor detection, screening, and prognostication. While the identification of oncogenes and biomarkers from circulating tumor cells or tissue biopsies is currently standard practice for cancer diagnosis and classification, accumulating evidence underscores the significant role of epigenetics in regulating stem cell fate, including proliferation, self-renewal, and malignant transformation. This highlights the importance of analyzing the methylome, exosomes, and circulating RNA for detecting cellular transformation. The development of diagnostic assays that integrate liquid biopsies with epigenetic analysis holds immense potential for revolutionizing tumor management by enabling rapid, non-invasive diagnosis, real-time monitoring, and personalized treatment decisions. This review covers current studies exploring the use of epigenetic regulation, specifically the methylome and circulating RNA, as diagnostic tools derived from liquid biopsies. This approach shows promise in facilitating the differentiation between primary central nervous system lymphoma and other central nervous system tumors and may enable the detection and monitoring of acute myeloid/lymphoid leukemia. We also discuss the current limitations hindering the rapid clinical translation of these technologies. Full article

Background and Objectives: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the aberrant proliferation of immature lymphoid cells. Lymphoblasts derived from the B-cell lymphoid lineage are identified as B-ALL. A20, CYLD and Cezanne are deubiquitinase genes that inhibit inflammatory response and tumor progression. Age-related increases in tumor necrosis factor (TNF)-α are associated with poor outcomes in ALL. Little is known about the associations of A20, CYLD and Cezanne with leukocyte accumulation in B-ALL. Materials and Methods: Blood samples of 147 patients with B-ALL and 144 healthy subjects were examined. Gene expression profiles were determined by quantitative PCR, gene polymorphisms by direct DNA sequencing, immunophenotype by flow cytometry and secretion of inflammatory cytokines by an ELISA. Results: Genetic analysis of the A20 gene identified six nucleotide changes in exon 7. Sequencing of the Cezanne gene identified three variants in intron 10. The results indicated that B-ALL patients carrying the A20 p.P348L and Cezanne rs1230581026 variants had higher variant frequencies and lower expression levels than healthy controls. Importantly, carriers of the A20 p.P348L variant had a higher numbers of CD20⁺ and HLA DR⁺ cells than those with a normal genotype, and carriers of the Cezanne rs1230581026 variant had increases in neutrophil, basophil, monocyte, lymphocyte, and CD38⁺ cell counts as well as age-related increases in the levels of TNF-α. Conclusions: The results indicate that the A20 p.P348L and Cezanne rs1230581026 variants are associated with low expression levels of A20/Cezanne, leukocyte expansion and poor outcomes in B-ALL patients. Full article

MicroRNAs are key regulators of lymphoid differentiation, exhibiting a pivotal role in acute lymphoblastic leukemia (ALL) biology and prognosis. The initial steps of canonical miRNA biogenesis involve the microprocessor complex processing the primary miRNA transcripts into precursor miRNAs via Drosha. DROSHA polymorphisms have been implicated in pediatric ALL and linked with cancer risk. This study investigated the role of rs642321, rs3805500, and rs10035440 DROSHA polymorphisms in ALL susceptibility, relapse, and outcomes in children and adolescents of Greek descent. The study included 252 children and adolescents (115 ALL cases and 137 controls). Genotyping was performed using RT-qPCR and the TaqMan Genotyping Assay. Homozygotes for the minor allele in DROSHA rs642321 were nominally associated with ALL susceptibility (TT vs. CC+CT; OR 4.5; 95% CI: 1.2–21.2; p_adj = 0.034). Likewise, homozygotes for the minor allele in rs3805500 were linked with ALL risk (GG vs. AA+AG; OR 2.7; 95% CI: 1.3–6.1; p_adj = 0.012). A suggestive association was observed between the rs3805500 AG genotype and both relapsed (OR 5.8; 95% CI: 1.6–24.3; p_adj = 0.011) and deceased cases (OR 5; 95% CI: 1.1–26.3; p_adj = 0.038). Patients with the rs3805500 AG and GG genotypes showed a trend toward poorer overall survival rates. In summary, certain haplotypes of DROSHA polymorphisms may be modestly associated with the occurrence of childhood ALL and its outcomes, although these findings require validation in larger, independent cohorts. Full article

The nucleoprotein structures known as telomeres provide genomic integrity by protecting the ends of chromosomes. Tumorigenesis is associated with alterations in telomere function and stability. This narrative review provides evidence of the potential prognostic value of telomere length and telomerase in leukemias. On the one hand, oxidative stress and mitochondrial dysfunction can accelerate telomere shortening, leading to higher susceptibility and the progression of leukemia. On the other hand, cytogenetic alterations (such as gene fusions and chromosomal abnormalities) and genomic complexity can result from checkpoint dysregulation, the induction of the DNA damage response (DDR), and defective repair signaling at telomeres. This review thoroughly outlines the ways by which telomere dysfunction can play a key role in the development and progression of four primary leukemias, including chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and acute leukemias of myeloid or lymphoid origin, highlighting the potential prognostic value of telomere length in this field. However, telomerase, which is highly active in leukemias, can prevent the rate of telomere attrition. In line with this, leukemia cells can proliferate, suggesting telomerase as a promising therapeutic target in leukemias. For this reason, telomerase-based immunotherapy is analyzed in the fight against leukemias, leveraging the immune system to eliminate leukemia cells with uncontrolled proliferation. Full article

Leukemia constitutes approximately one-third of all pediatric cancers, with acute lymphoblastic leukemia (ALL) comprising roughly 80% of pediatric leukemia instances. This study sought to ascertain the prevalence of HLA A, B, DR, and DQ allele groups linked with pediatric acute leukemia. We recruited 70 Moroccan children diagnosed with acute lymphoblastic leukemia (ALL), 39 of whom had BCP-ALL and were eligible for hematopoietic stem cell transplantation, compared to a control group of 136 healthy children. Patients and controls were subjected to HLA class I and II typing, utilizing either sequence-specific primers (SSPs) or sequence-specific oligonucleotides (SSOs) in polymerase chain reaction-based techniques. The findings indicated significantly elevated frequencies of HLA-A*68 and B*14 in pediatric patients with ALL relative to the control group (p = 0.001 and p = 0.02, respectively). The frequencies of HLA-DRB1*01 and DQB1*05 allele groups were considerably elevated in children with ALL and BCP-ALL compared to the controls (p < 0.01 for both). The findings of our study indicate that HLA-A*68, -B*14, -DRB1*01, and DQB1*05 may serve as potential predisposing immunogenetic variables for the development of juvenile acute lymphoblastic leukemia (ALL). Nonetheless, additional research including a bigger sample considering other regions of Morocco would be beneficial to more accurately delineate the association between the HLA system and ALL. Full article

CD300 family members are immunoglobulin superfamily receptors that regulate immune cell function through either activating or inhibitory signals. Among them, CD300a is a prototypical inhibitory receptor, highly expressed in both myeloid and lymphoid lineages, and plays a pivotal role in the pathogenesis of inflammation and tumor immunity. CD300a transduces inhibitory signals in several immune cells—including mast cells, eosinophils, monocytes, dendritic cells (DCs), neutrophils, and natural killer (NK) cells—by recruiting SHP-1 phosphatase to immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and suppressing activation pathways such as Toll-like receptor (TLR)-MyD88 and FcεRI signaling. Recent studies suggest that tumor cells may hijack CD300a-associated pathways to establish an immunosuppressive microenvironment that facilitates immune evasion, tumor survival, and potentially metastatic spread. Proposed mechanisms include reduced DC-mediated type I interferon (IFN) production, diminished NK cell cytotoxicity, and negative regulation of mast cell– and eosinophil-dependent anti-tumor responses. Although some of these findings are derived from in vivo models, the cumulative evidence positions CD300a as a critical immune checkpoint in tumor-associated immune regulation. In addition to its established roles in hematologic malignancies—including chronic lymphocytic leukemia, acute lymphoblastic leukemia, and acute myeloid leukemia—CD300a has also been implicated in modulating tumor-associated immune responses in other pathological contexts. While most studies emphasize its immune cell–mediated effects, emerging evidence suggests that CD300a may directly influence tumor progression by regulating immune homeostasis, intracellular signaling, and tumor microenvironment interactions. Collectively, these findings establish CD300a as a pleiotropic immunoregulatory molecule in both hematologic and non-hematologic malignancies, underscoring the need to further explore its broader relevance and therapeutic potential in cancer immunology. Full article

Liquid biopsy is classically defined as the detection of biomarkers in bodily fluids. One of these biomarkers can be circulating cell-free DNA (cfDNA) released by healthy or cancer cells during apoptosis. These fragments can be quantified and molecularly characterized by techniques like digital droplet PCR (ddPCR) or next-generation sequencing (NGS). By identifying common genetic and epigenetic alterations associated with specific cancer types, cfDNA or circulating tumor DNA (ctDNA) can serve as robust biomarkers for monitoring tumor initiation and progression. Other biomarkers, such as circulating microRNAs (miRNAs), extracellular vesicles, or circulating tumor cells (CTCs) are also applied in this context. Liquid biopsy has gained attention as a versatile tool for cancer diagnostics, prognosis, therapeutic monitoring, and minimal residual disease (MRD) detection across various malignancies, including hematological cancers like myeloid and lymphoid leukemias. Herein, we present a comprehensive review of liquid biopsy usage in leukemia, with a specific focus on the clinical utility of ctDNA, miRNAs, and exosomes in monitoring treatment response, tracking clonal evolution, and detecting minimal residual disease. Our review emphasizes the translational implications of these tools for improving patient outcomes and outlines current challenges in their integration into clinical practice. Full article

The analysis of tumor metabolism offers promising opportunities for developing new therapeutic strategies. Plant-derived polymolecular drugs can regulate cellular metabolism, making them potential candidates for treatment. This study examined the metabolic effects of plant-derived polymolecular drugs—P2Et, Anamu-SC, and Esperanza—on leukemic cell lines (lymphoid and myeloid types) and primary leukemic blasts. The metabolic analysis included oxidative status, glucose consumption, extracellular acidification, oxygen consumption, mitochondrial dynamics, and untargeted metabolomics. Additionally, the effect of co-treatment with conventional chemotherapeutic drugs was investigated. Results showed that P2Et and Anamu-SC reduced the viability and proliferation of all tumor cell lines, exhibiting antioxidant effects. Anamu-SC decreased reactive oxygen species levels in lymphoid tumor cells. Mitochondrial activity was selectively affected by the plant-derived polymolecular drugs, with Anamu-SC and Esperanza causing more significant, potentially reversible damage compared to P2Et. Anamu-SC and Esperanza increased levels of phosphatidylcholines and carnitines. The co-administration of plant-derived polymolecular drugs with chemotherapeutics improved the cytostatic efficacy of cytarabine. In conclusion, this research highlights the promising pharmacological activity of Anamu-SC and Esperanza as mitocans for the treatment of acute leukemia. The study emphasizes the practical significance of combining plant-derived polymolecular drugs with conventional chemotherapeutics to enhance their cytostatic efficacy. Full article

Background/Objectives: Minimal residual disease (MRD) refers to the resistant clonal population of leukemia cells that survive induction chemotherapy, serving as a critical indicator of treatment response in pediatric Acute Lymphoid Leukemia (ALL). While flow cytometry (FCM) and molecular methods are standard for MRD detection, novel leukemia-associated immunophenotype (LAIP) markers are needed when conventional markers are insufficient. Methods: MRD was assessed in 218 pediatric B-ALL patients using a combinatory approach of Different-from-Normal (DfN) and LAIP strategies. An eight-color flow cytometry panel included routine MRD markers (e.g., CD10, CD19, and CD20) and less commonly used markers (e.g., CD123, CD73, CD86). Cytogenetic and molecular profiling were integrated to evaluate the association between genetic abnormalities and MRD positivity. Results: The combined DfN and LAIP approach enhanced MRD detection sensitivity compared to individual methods. CD7 showed a significant association with MRD positivity (p = 0.003), whereas CD73 (p = 0.000) and CD86 (p = 0.002) correlated with MRD-negative status. CD123 exhibited the highest aberrancy among MRD-positive cases, while CD81 had the lowest. These findings highlight the prognostic potential of CD73 and CD86 for MRD-negative status, complementing the established utility of CD123. Conclusions: Incorporating novel markers (CD123, CD73, CD86, and CD81) into MRD panels enhances detection sensitivity and clinical applicability. These markers are compatible with standard flow cytometry, supporting their integration into routine practice for comprehensive MRD evaluation, ultimately improving therapeutic outcomes in pediatric B-ALL. Full article

Sialic acids serve as crucial terminal sugars on glycoproteins or glycolipids present on cell surfaces. These sugars are involved in diverse physiological and pathological processes through their interactions with carbohydrate-binding proteins, facilitating cell–cell communication and influencing the outcomes of bacterial and viral infections. The role of hypersialylation in tumor growth and metastasis has been widely studied. Recent research has highlighted the significance of aberrant sialylation in enabling tumor cells to escape immune surveillance and sustain their malignant behavior. Acute lymphoblastic leukemia (ALL) is a heterogenous hematological malignancy that primarily affects children and is the second leading cause of mortality among individuals aged 1 to 14. ALL is characterized by the uncontrolled proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and various organs. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are cell surface proteins that can bind to sialic acids. Activation of Siglecs triggers downstream reactions, including induction of cell apoptosis. Siglec-7 and Siglec-9 have been reported to promote cancer progression by driving macrophage polarization, and their expressions on natural killer cells can inhibit tumor cell death. This comprehensive review aims to explore the sialylation mechanisms and their effects on ALL in children. Understanding the complex interplay between sialylation and ALL holds great potential for developing novel diagnostic tools and therapeutic interventions in managing this pediatric malignancy. Full article

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, comprising almost 25% of all malignancies diagnosed in children younger than 20 years, and its incidence is still increasing. ALL is a blood cancer arising from the unregulated proliferation of clonal lymphoid progenitor cells. To make a diagnosis of B-cell ALL, bone marrow morphology and immunophenotyping are needed; cerebrospinal fluid examination, and chromosomal analysis are currently used as stratification exams. Currently, almost 70% of children affected by B-cell ALL are characterized by well-known cytogenetic abnormalities. However, the integration of results with “omic” techniques (genomics, transcriptomics, proteomics, and metabolomics, both individually and integrated) able to analyze simultaneously thousands of molecules, has enabled a deeper definition of the molecular scenario of B-cell ALL and the identification of new genetic alterations. Studies based on omics have greatly deepened our knowledge of ALL, expanding the horizon from the traditional morphologic and cytogenetic point of view. In this review, we focus our attention on the “omic” approaches mainly used to improve the understanding and management of B-cell ALL, crucial for the diagnosis, prognosis, and treatment of the disease, offering a pathway toward more precise and personalized therapeutic interventions. Full article

Acute lymphoblastic leukemia (ALL) is a malignant condition of lymphoid progenitor cells that primarily affects the pediatric population, but also adults. The 5-year survival rate is 90% in children and approximately 40% in adults, with survival increasing through the use of peripheral stem cell allotransplantation (SCT). The relapse rate after stem cell transplantation (SCT) in adult acute lymphoblastic leukemia (ALL) patients ranges from 35% to 45%, making relapse a major cause of death in this population. Background: We present an atypical case of late testicular involvement in ALL in a 50-year-old man diagnosed with ALL pro-T in remission post-chemotherapy (GMALL 2003 protocol) and allogeneic stem cell transplantation (alloSCT) from a related donor. Methods: This case describes a 50-year-old male with ALL pro-T who experienced three rare extramedullary relapses post-chemotherapy and alloSCT. Five years after remission, he had a unilateral testicular relapse confirmed by immunophenotyping of spermatic fluid. Results: Despite no bone marrow involvement, he was treated with chemotherapy, intrathecal therapy, and bilateral testicular radiotherapy. He later relapsed in the orbit, controlled by radiotherapy, followed by a third relapse in the heart and colon. Conclusions: This case highlights the unusual sites and consecutive nature of extramedullary relapses in adult ALL. Full article

Despite the advances of CAR-T cells in certain hematological malignancies, mostly from B-cell derivations such as non-Hodgkin lymphomas, acute lymphoblastic leukemia and multiple myeloma, a significant portion of other hematological and non-hematological pathologies can benefit from this innovative treatment, as the results of clinical studies are demonstrating. The clinical application of CAR-T in the setting of acute T-lymphoid leukemia, acute myeloid leukemia, solid tumors, autoimmune diseases and infections has encountered limitations that are different from those of hematological B-cell diseases. To overcome these restrictions, strategies based on different molecular engineering platforms have been devised and will be illustrated below. The aim of this manuscript is to provide an overview of the CAR-T application in pathologies other than those currently treated, highlighting both the limits and results obtained with these settings. Full article

Background: Recent advances in childhood acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) management provide higher survival rates at the cost of increased toxicities. Acute neurotoxicity affects up to 10% of patients, requiring rapid recognition and treatment. Methods: A retrospective observational study was performed to determine the frequency, clinical manifestations, radiological characteristics, treatment options and outcome of acute neurological adverse events in pediatric patients with lymphoid malignancies at the Department of Oncology and Hematology, Children’s Hospital Zagreb, Croatia. Results: A total of 56 patients (48 ALL and 8 LL, male/female ratio 1:1, average age 5.4 years) were treated mainly according to the ALL-IC BFM 2009 protocol. The B-immunophenotype was the most frequent (85.7%). Most patients were stratified to the intermediate risk group (39.3%), and two were initially diagnosed with central nervous system infiltration. Acute neurotoxic events were registered in 11 patients (19.6%), most commonly in the 6–10-year age group (66.7%), predominately in females (72.7%) and high-risk group (54.5%). The most frequent clinical presentation was seizures (83.3%), with status epilepticus in four cases. We detected electroencephalogram (EEG) irregularities in almost all patients and various morphological changes in the brain magnetic resonance imaging (MRI), most often consistent with posterior reversible encephalopathy syndrome and leukoencephalopathy. Approximately half the patients received prolonged antiepileptic therapy. No apparent residual neurologic manifestations have been observed. Conclusions: Acute neurotoxicity is a rather frequent treatment-related adverse event, associated with high-risk disease. Early recognition and timely management are essential for rapid recovery and optimal outcomes. Full article