Search Results (328)

Background: Cannabidiol (CBD) is a major non-psychoactive phytocannabinoid that exerts multiple biological effects in the body. It has been shown to exert anti-cancer effects in a variety of cancer cells, including acute lymphoblastic leukemia of pre-T cell origin (T-ALL), a highly aggressive hematological malignancy. However, the mechanisms underlying CBD’s anti-cancer effects are not fully understood. Furthermore, cancer cells abundantly express surface CD47, which is a negative regulator of phagocytosis and linked with cell survival/death. Little is known about CBD effects on the expression of CD47 in T-ALL cells. The objectives of this study were to address these issues. Methods: Studies were conducted in vitro using Jurkat cells and human peripheral blood mononuclear cells in different culture conditions, CBD concentrations, and in the presence or absence of different reagents. Results: CBD downregulates CD47 expression and induces apoptosis in Jurkat cells. Similar biological effects of CBD were also observed in primary human CD4⁺ T cells, albeit at reduced levels. The CBD’s effects on CD47 expression and apoptosis were not rescued by a cannabinoid receptor (CBR)-2 agonist, a CBR-2 antagonist, or an anion channel blocker. However, these effects on CD47 expression and apoptosis were significantly rescued by a Voltage-Dependent Anion Channel (VDAC)-1 oligomerization inhibitor. Conclusions: Overall, we conclude that CBD downregulates CD47 expression and induces apoptosis involving VDAC-1 oligomerization. Furthermore, they also suggest that CBD’s pro-apoptotic effects on primary human T cells should also be monitored if it is used as an anti-cancer adjuvant or neo-adjuvant therapeutic in cancer patients. Full article

Acute myeloid leukemia (AML) is an aggressive cancer with rapid progression and a high relapse rate, highlighting the urgent need for effective treatments. While recent advances in drug therapies and combination regimens have improved outcomes, relapsed and refractory (R/R) AML still shows low response rates, poor prognosis, and limited survival. The lack of effective immunotherapies further complicates the management of R/R AML. The bone marrow tumor microenvironment (TME) poses a significant barrier, requiring multifaceted, combined therapeutic strategies for clinical success. This TME creates an immunosuppressive and metabolically challenging environment that limits the expansion, persistence, cytotoxicity, and survival of chimeric antigen receptor (CAR) T cells. Unlike CD19 in B-cell acute lymphoblastic leukemia (B-ALL), AML lacks a truly leukemia-specific antigen. Although clinical trials are ongoing, no CAR-T therapies have received FDA approval for AML. This paper explores the reasons behind these ongoing challenges. Full article

While the PI3K/Akt/mTOR pathway is a well-established drug target in T-cell acute lymphoblastic leukemia (T-ALL), the contribution of the Hedgehog (Hh) pathway in T-ALL malignancy remains poorly defined. We investigated the effects of pharmacological inhibition of key signaling nodes in these pathways using T-ALL cell lines (Jurkat, Molt-4, DND-41, and ALL-SIL). Cells were treated with the Gli1 inhibitor Gant-61, the Smoothened inhibitors GDC-0449 and Glasdegib, the Akt inhibitor MK-2206, and the mTOR inhibitor RAD001, both alone and in combination. Analyses of cell viability, cell cycle progression, apoptosis, autophagy, protein expression, and in situ intracellular distribution revealed potent cytotoxic activity of Gant-61 and MK-2206, while Smo and mTOR inhibitors showed limited efficacy. Combined Gli1 and Akt inhibition induced synergistic suppression of proliferation, enhanced G0/G1 arrest, increased apoptosis, and promoted autophagy, accompanied by reduced nuclear Gli1 and decreased Akt phosphorylation. These findings demonstrate a functional interaction between Hh/Gli1 and PI3K/Akt pathways in T-ALL and identify Gli1 as a critical, druggable node. Dual targeting of Gli1 and Akt represents a potential therapeutic strategy to overcome resistance and improve treatment outcomes in T-ALL. Full article

KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL), particularly in infants, represents one of the most aggressive pediatric hematological malignancies with a historically dismal prognosis. While KMT2A-AFF1 (t(4;11)) is the most prevalent fusion, a diverse array of partner genes exists, each conferring distinct biological and clinical features. This review focuses on the rare but clinically significant KMT2A-AFF3 subtype, which arises from the t(2;11)(q11.2;q23) chromosomal translocation. This review summarizes the molecular pathogenesis driven by the KMT2A-AFF3 fusion oncoprotein, which functions as an aberrant transcriptional complex. This complex hijacks essential epigenetic machinery, including the recruitment of DOT1L and interaction with Menin, leading to pathogenic histone modifications (e.g., H3K79 hypermethylation) and the subsequent upregulation of critical target genes, notably the HOXA cluster and MEIS1, thereby enforcing a B-lymphoid differentiation arrest at the pro-B/pre-B stage. Clinically, KMT2A-AFF3 ALL is characterized by high-risk features, including infant onset, hyperleukocytosis, central nervous system (CNS) involvement, and a distinct CD10-negative immunophenotype. This review highlights the evidence defining its poor prognosis, which is primarily driven by profound chemoresistance to conventional therapies, including glucocorticoids. Finally, we discuss the rapidly evolving therapeutic landscape, detailing the limitations of standard intensive chemotherapy and the immense promise of novel targeted strategies, such as Menin inhibitors (e.g., Revumenib), DOT1L inhibitors, and immunotherapies (e.g., CAR-T cells, Blinatumomab), which hold the potential to revolutionize outcomes for this high-risk leukemia subtype. Full article

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, characterized by the clonal proliferation of immature lymphoid precursors. The distinction between B-cell ALL (B-ALL) and T-cell ALL (T-ALL) is fundamental, as each subtype exhibits distinct cytomorphological, genetic, and clinical features influencing prognosis and therapeutic strategies. Conventional multi-phase chemotherapy has significantly improved survival rates, yet its efficacy is limited by severe short- and long-term toxicities, highlighting the need for more selective therapeutic approaches. Advances in molecular profiling have enabled the identification of key oncogenic pathways, paving the way for targeted therapies such as tyrosine kinase inhibitors (TKIs), JAK-STAT pathway inhibitors, BCL-2 antagonists, and agents modulating epigenetic and cell cycle regulators. Concurrently, immunotherapeutic strategies have transformed the therapeutic landscape of pediatric ALL. Bispecific antibodies such as blinatumomab (anti-CD19), antibody–drug conjugates like inotuzumab ozogamicin (anti-CD22), and monoclonal antibodies such as daratumumab (anti-CD38) have demonstrated efficacy in relapsed or refractory disease with improved safety profiles. Moreover, CAR-T-cell therapy, particularly CD19-directed products, has shown unprecedented remission rates in refractory B-ALL. The integration of targeted and immune-based therapies into conventional regimens represents a decisive step toward precision medicine, aiming to enhance survival outcomes while reducing treatment-related toxicity and improving quality of life in ALL children. This review aims to provide a comprehensive overview of the current understanding of ALL pathobiology and therapeutic approaches, with particular emphasis on the expanding role of immunotherapeutic strategies in pediatric disease. Full article

Background/Objectives: Asparaginase (ASP)-based chemotherapy has substantially improved clinical outcomes in Epstein–Barr virus (EBV)-positive NK/T-cell lymphomas (NKTCL). However, as a bacterial-derived enzyme, ASP is frequently associated with immune-mediated adverse events, particularly hypersensitivity reactions (HSRs), which may compromise both treatment efficacy and patient safety. This report presents a case of an ASP-related HSR and reviews the incidence within our institutional cohort. Detailed Case Description: A 60-year-old female presented an immediate Grade 2 HSR during her second PEG-asparaginase infusion, with pruritus, vomiting, and presyncope. The infusion was discontinued, and she was subsequently transitioned to crisantaspase—an alternative formulation—which was well tolerated without further adverse events. She remains disease-free to date. A retrospective review of institutional records (2015–2025) identified six patients with NKTCL treated with ASP-containing chemotherapy. The incidence of HSRs in this cohort was 1 of 6 (16.7%). Conclusions: As in acute lymphoblastic leukemia, HSRs to asparaginase remains a major challenge in the management of NKTCL with potential implications for treatment safety and efficacy. The establishment of standardized, consensus-based criteria for the diagnosis, classification, and management of ASP-related HSRs is urgently needed to optimize patient outcomes. Full article

Childhood acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and while chemotherapy has significantly improved survival rates, it can also lead to long-term side effects, including immune system dysfunction. This study aimed to investigate in detail, using flow cytometry, the T-cell subpopulations in the peripheral blood of children who have completed ALL treatment and compare them to a group of healthy children. The study group consisted of 20 patients, aged 5 to 18 years, with blood samples collected at least one year after treatment completion. Of the 52 T-cell subpopulations analyzed, 16 showed statistically significant differences. Children after ALL treatment had lower absolute values of TCRγδ+ and higher values of double-positive CD4+CD8+ and CD8+ T cells. They also had higher absolute numbers of memory T cells, including total CD45RO+ T cells, and the CD45RO+CD8+ and CD45RO+CD27+ subpopulations. Furthermore, post treatment patients showed higher absolute values of activated T cells (HLA-DR+, HLA-DR+CD8+, HLA-DR+CD57+, and CD25+CD8+), as well as CD57+ and CCR7+ T cells. The absolute leukocyte and granulocyte counts were lower in the study group, while the total lymphocyte count was significantly higher compared to the control group. The findings indicate persistent changes in T-cell subpopulations after ALL treatment, suggesting ongoing immune system rebuilding and chronic antigenic stimulation, possibly due to viral reactivation or chemotherapy-related tissue damage. The increased number of TCRγδ+ cells, which are responsible for eliminating cancer cells, may be a positive aspect of this rebuilding. Full article

L-asparaginase (L-ASNase) is a vital enzymatic drug widely used for treating acute lymphoblastic leukemia (ALL) and certain lymphomas. However, its clinical application is often limited by a short plasma half-life, pronounced immunogenicity, and systemic toxicities. To address these challenges, we recently developed conjugates of L-ASNase with cationic polymers, enhancing its cytostatic activity by increasing enzyme binding with cancer cells. The present study focuses on the development of liposomal formulations of E. coli L-asparaginase (EcA) and its conjugates with cationic polymers: the natural oligoamine spermine (spm) and a synthetic polyethylenimine–polyethyleneglycol (PEI-PEG) copolymer. This approach aims to improve enzyme encapsulation efficiency and stability within liposomes. Various formulations—including EcA conjugates with polycations incorporated into 100 nm and 400 nm phosphatidylcholine/cardiolipin (PC/CL, 80/20) anionic liposomes—were synthesized as a delivery system of high enzyme load. Fourier Transform Infrared (FTIR) spectroscopy confirmed successful enzyme association with liposomal carriers by identifying characteristic changes in the vibrational bands corresponding to both protein and lipid components. In vitro release studies demonstrated that encapsulating EcA formulations in liposomes more than doubled their half-release time (T_1/2), depending on the formulation. Cytotoxicity assays against Raji lymphoma cells revealed that liposomal formulations, particularly 100 nm EcA-spm liposomes, exhibited markedly superior anti-proliferative activity, reducing cell viability to 4.5%, compared to 35% for free EcA. Confocal Laser Scanning Microscopy (CLSM) provided clear visual and quantitative evidence that enhanced cellular internalization of the enzyme correlates directly with its cytostatic efficacy. Notably, formulations showing higher intracellular uptake produced greater cytotoxic effects, emphasizing that hydrolysis of asparagine inside cancer cells, rather than extracellularly, is critical for therapeutic success. Among all tested formulations, the EcA-spermine liposomal conjugate demonstrated the highest fluorescence intensity within cells providing enhanced cytotoxicity. These results strongly indicate that encapsulating cationically modified L-ASNase in liposomes is a highly promising strategy to improve targeted cellular delivery and prolonged enzymatic activity. This strategy holds significant potential for developing more effective and safer antileukemic therapies. Full article

Pre-B-cell leukemia factor 1 (PBX1) is a transcription factor that plays a significant role in various physiological, developmental, and oncogenic processes in humans. The mechanisms and interactions of PBX1 in both solid and hematologic malignancies remain significant areas of study. It was initially found in pre-B-cell acute lymphoblastic leukemia as a result of the chromosomal translocation t(1;19). Over the years, its role in other blood neoplasms has been studied. PBX1 and its variant E2A::PBX1 regulate gene expression that influences cell proliferation and differentiation in hematopoietic lineages. Their interaction with oncogenic partners results in abnormal gene regulation and tumorigenesis. Research has predominantly focused on the role of these factors in leukemias and plasma cell neoplasms, whereas other hematologic neoplasms have been largely overlooked. The potential application of PBX1 as a prognostic and predictive biomarker has recently gained attention. However, further research is needed to fully understand its complex role and how it can be targeted for therapeutic purposes. This review summarizes current knowledge on PBX1’s role in the growth of both mature and immature hematologic neoplasms. Moreover, it focuses on its prospective use as a therapeutic target and to predict prognosis, especially for aggressive neoplasms that do not respond to current therapeutic approaches. Full article

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, typically presenting with systemic symptoms and mediastinal involvement. Leukemia cutis (LC) and renal infiltration are rare, especially at disease onset. A 27-year-old man presented with a solitary scalp lesion without systemic symptoms or hematologic abnormalities. Histopathology revealed a blastoid lymphoid infiltrate with a T-ALL immunophenotype. Two weeks later, laboratory tests showed leukocytosis, lymphocytosis, and renal dysfunction. Imaging revealed a large mediastinal mass, scalp soft tissue involvement, and bilateral renal infiltration. Bone marrow biopsy confirmed T-ALL with a mature phenotype. FISH identified TRAD:NKX2 rearrangement and CDKN2AB deletion. The patient received three cycles of pediatric-inspired chemotherapy, achieving complete molecular remission and resolution of extramedullary disease. He subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-matched sibling. Post-transplant complications included febrile neutropenia and mucositis. On day +100, he remained in minimal residual disease (MRD)-negative remission. This case illustrates a rare presentation of T-ALL with isolated skin involvement and renal infiltration at diagnosis, highlighting the importance of early biopsy and immunophenotyping of atypical skin lesions. Intensive chemotherapy followed by HSCT represents a viable strategy for young adults with high-risk T-ALL and extramedullary disease. Full article

In the past decades, significant advancements in the biological and genetic characterization of acute leukemias and optimization of risk-adapted multi-agent treatment protocols have dramatically improved cure rates and quality of life for children with acute lymphoblastic leukemia (ALL). Despite these optimal results, patients with relapsed or chemotherapy-refractory (R/R) disease or with high-risk genetic features still face unsatisfactory outcomes. Further intensification of conventional chemotherapy has reached its limits in achieving the desired efficacy without undue side effects, necessitating innovative approaches to improve cure rates while continuing to minimize the toxicities associated with chemotherapy and hematopoietic stem cell transplantation. In the era of precision medicine, two key therapeutic strategies have emerged in hemato-oncology: molecularly targeted therapies and immunotherapies. Antibody-based and cellular immunotherapies have undoubtedly reshaped the landscape of childhood ALL treatment and have significant potential to play leading roles in current and future frontline regimens; these important therapies are well delineated in recent reviews. Molecularly targeted small molecule inhibitor therapies remain a cornerstone of precision medicine, supported by recent advancements in next-generation sequencing, which have enabled the application of transcriptomic and genomic profiling data to risk stratification and therapy optimization. Clinical trials for children with ALL have been instrumental in refining therapies and improving outcomes, a paradigm that remains critical as treatment strategies become increasingly complex. This comprehensive review focuses upon molecularly targeted therapy approaches for childhood ALL and aims to summarize findings from completed clinical trials to highlight the current landscape of ongoing and upcoming trials and to provide insights into future directions for the precision-driven optimization of pediatric B-ALL and T-ALL treatment. Full article

B-cell acute lymphoblastic leukemia (B-ALL) is characterized by the abnormal proliferation of B-lineage lymphocytes in the bone marrow (BM). The roles of immune cells within the BM microenvironment remain incompletely understood. Single-cell RNA sequencing (scRNA-seq) provides the potential for groundbreaking insights into the pathogenesis of B-ALL. In this study, scRNA-seq was conducted on BM samples from 17 B-ALL patients (B-ALL cohorts) and 13 healthy controls (HCs). Bioinformatics analyses, including clustering, differential expression, pathway analysis, and gene set variation analysis, systematically identified immune cell types and assessed T-cell prognostic and metabolic heterogeneity. A metabolic-feature-based machine learning model was developed for B-ALL subtyping. Furthermore, T-cell–monocyte interactions, transcription factor (TF) activity, and drug enrichment analyses were performed to identify therapeutic targets. The results indicated significant increases in Pro-B cells, alongside decreases in B cells, NK cells, monocytes, and plasmacytoid dendritic cells (pDCs) among B-ALL patients, suggesting immune dysfunction. Clinical prognosis correlated significantly with the distribution of T-cell subsets. Metabolic heterogeneity categorized patients into four distinct groups (A–D), all exhibiting enhanced major histocompatibility class I (MHC-I)-mediated intercellular communication. The metabolic-based machine learning model achieved precise classification of B-ALL groups. Analysis of TF activity underscored the critical roles of MYC, STAT3, and TCF7 within the B-ALL immunometabolic network. Drug targeting studies revealed that dorlimomab aritox and palbociclib specifically target dysregulation in ribosomal and CDK4/6 pathways, offering novel therapeutic avenues. This study elucidates immunometabolic dysregulation in B-ALL, characterized by altered cellular composition, metabolic disturbances, and abnormal cellular interactions. Key TFs were identified, and targeted drug profiles were established, demonstrating the significant clinical potential of integrating immunological mechanisms with metabolic regulation for the treatment of B-ALL. Full article

(1) Background: Methylobacterium radiotolerans (M. radiotolerans) is a fastidious, aerobic, Gram-negative bacillus primarily found in environmental sources such as soil and sewage, with rare clinical isolation. Its identification remains challenging due to poor growth with conventional culture methods. (2) Case presentation: A 42-year-old male patient with early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) presented with M. radiotolerans bacteremia during hospitalization. The organism was successfully isolated from peripheral blood using the Myco/F Lytic culture vial (Becton, Dickinson and Company, Lincoln, MT, USA). Comparative analysis demonstrated markedly superior growth of M. radiotolerans in Myco/F Lytic culture vials compared with Plus Aerobic/F Lytic and Lytic/10 Anaerobic/F culture vials (Becton, Dickinson and Company, Lincoln, MT, USA). Antimicrobial susceptibility testing, performed with the epsilometer test (E-test) and Bauer–Kirby disk diffusion (BK) method, guided the selection of an appropriate therapeutic regimen. The patient’s infection was ultimately controlled following targeted antimicrobial therapy. (3) Conclusions: M. radiotolerans demonstrates a distinct growth preference for the Myco/F Lytic culture medium. This observation highlights the importance of considering alternative culture media in cases of rare or fastidious bacterial infections that cannot be reliably detected using conventional Plus Aerobic/F Lytic or Lytic/10 Anaerobic/F culture vials, which are typically employed for clinical isolation of aerobic and anaerobic bacteria. Full article

Background: Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-cell ALL characterized by a gene expression profile similar to BCR::ABL1-positive leukemia, but lacking the BCR::ABL1 fusion gene. It is frequently associated with kinase-activating alterations, such as CRLF2 rearrangements, JAK-STAT pathway mutations, and ABL-class fusions. Patients with Ph-like ALL typically experience poor outcomes with conventional chemotherapy, underscoring the need for intensified and targeted therapeutic approaches. Methods: This review summarizes current evidence regarding the role of hematopoietic stem cell transplantation (HSCT) in patients with Ph-like ALL. We analyzed retrospective cohort studies, registry data, and ongoing clinical trials, focusing on transplant indications, molecular risk stratification, measurable residual disease (MRD) status, timing of transplant, and post-transplant strategies. Results: Retrospective data suggest that HSCT in first complete remission (CR1) may improve survival in patients with high-risk molecular lesions or MRD positivity at the end of induction. However, the lack of prospective data specific to Ph-like ALL limits definitive conclusions. Post-transplant relapse remains a challenge, and novel strategies, including the use of tyrosine kinase inhibitors or JAK inhibitors as post-HSCT maintenance therapy, are being explored. Emerging immunotherapies, such as chimeric antigen receptor (CAR) T cells, may reshape the therapeutic landscape and potentially alter the indications for transplantation. Conclusions: HSCT remains a crucial therapeutic option for selected patients with Ph-like ALL, particularly those with poor molecular risk features or persistent MRD. However, further prospective studies are needed to evaluate the indication for HSCT in CR1 and the potential integration of transplantation with targeted and immunotherapeutic strategies. Personalized treatment approaches based on genomic profiling and MRD assessment are essential to improve outcomes in this high-risk subset. Full article

Background: Although telomere length maintenance is a common characteristic of hematological malignancies, the role of telomere length as a prognostic factor to stratify acute lymphoblastic leukemia (ALL) patients depending on their risk of relapse remains elusive. Methods: This knowledge gap motivated us to examine telomere length values in children with ALL at the time of diagnosis and after treatment using quantitative polymerase chain reaction (qPCR) (n = 35). To achieve high-resolution precision and cell specificity, a quantitative fluorescence in situ hybridization (qFISH) technique was developed (n = 5). Results: The results demonstrated statistically significant evidence of telomere shortening in the lymphoblasts of children with ALL but not in the lymphocytes of children after remission following treatment. Our findings also suggested a significant association between telomere shortening and a high risk of relapse disease. Last but not least, our preliminary results showed a trend that telomere shortening was more pronounced in children with B-ALL compared to those with T-ALL in a non-significant manner. Conclusions: Consequently, the current study provides preliminary insights into the potentially substantial prognostic value of telomere length in the progression of pediatric ALL, with the possibility of predicting treatment response. To clarify the application of telomere length as a possible biomarker for disease progression and treatment response in children with ALL, the telomere length values of additional participants need to be examined in further studies. Full article