Search Results (47)

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Good overall survival rates of about 90% are the result of improvements in risk stratification and risk-adapted therapy, intensive chemotherapy regimens, hematopoietic stem cell transplantation, and better supportive care. Background and Objectives: The aim of this study is to review the epidemiology, prognostic factors, and causes of death in pediatric ALL patients treated at a tertiary care center, and to identify risk factors influencing clinical outcomes. Materials and Methods: A retrospective study was conducted at the Department of Pediatric Hematology and Oncology, University Hospital Centre Zagreb, including 302 children (0–18 years) diagnosed with ALL between January 2001 and December 2015. Results: Two hundred fifty-one children survived (5-year overall survival 83%). Relapse occurred in 13.6% of patients. Relapse rates were higher for B-cell precursor (Bcp)-ALL than for T-cell ALL (14.3% vs. 10.4%), and no patient with relapsed T-cell ALL survived. The main causes of death were refractory/relapsed disease (43% of patients), followed by infections (35%) and GVHD (8%). The most frequent causes of infectious death were Pseudomonas aeruginosa and Aspergillus fumigatus. The most critical treatment periods were the induction and reinduction phases, especially the de-escalation of corticosteroids. The time of relapse and risk group were independent factors in predicting the outcome. Conclusions: Relapse and infections were the leading causes of death in children with ALL, with the highest mortality observed during induction and reinduction phases. Survival was significantly influenced by relapse timing and risk group, with no survivors among relapsed T-ALL patients. 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

Measurable Residual Disease (MRD) assessment in pediatric acute lymphoblastic leukemia (ALL) is crucial for relapse prediction and treatment guidance. Multiparameter flow cytometry (MFC) enhances detection but faces limitations due to insufficient leukemia-associated immunophenotypes (LAIPs) and antigen modulation. This study explores new markers to improve MFC-based MRD detection in B-cell precursor ALL (BCP-ALL). Expression-patterns of seven aberrancy markers, i.e., CD44, CD304, CD73, CD86, CD123, CD99, CD58, and one B-cell maturation marker, CD22, were studied in 143 samples with leukemic-blasts from sixty-one childhood BCP-ALL patients and in hematogones of 20 non-leukemic bone marrow (BM) samples using fourteen-color MFC. The highest relative frequences of LAIPs amounted to 82.50%, reported for CD99 and CD58, followed by CD44 (81.10%), CD73 (76.20%), CD22 (73.40%), CD304 and CD86 (68.50%), while the lowest relative frequence was CD123 (44.40%). Differential expression of CD58, CD304, and CD73 in diagnostic samples was highly significant (p < 0.01) between pre-B-I, pre-B-II, immature B cells, and BCP-ALL blasts. In MRD-positive samples CD73 showed significantly high (p < 0.01) differential expression between all stages of hematogones and residual blasts, followed by CD304, CD58, and CD22. CD73 and CD304 were identified as the most reliable among the tested markers for distinguishing both diagnostic and MRD blasts from normal B cell precursors. Full article

Noonan syndrome (NS) is an autosomal dominant disorder that varies in severity and can involve multiple organ systems. In approximately 50% of cases, it is caused by missense mutations in the PTPN11 gene (12q24.13). NS is associated with a higher risk of cancer occurrence, specifically hematological disorders. Here, we report a case of a child who was diagnosed at birth with a transient myeloproliferative disorder (TMD). After two years, the child developed hyperdiploid B-cell precursor acute lymphoblastic leukemia (BCP-ALL), receiving a two-year course of treatment. During her continuous complete remission (CCR), a heterozygous germline mutation in the PTPN11 gene [c.218 C>T (p.Thr73lle)] was identified. At the age of ten, the child presented with massive splenomegaly, hyperleukocytosis, and thrombocytopenia, resulting in the diagnosis of juvenile myelomonocytic leukemia (JMML). After an initial response to antimetabolite therapy (6-mercaptopurine), she underwent haploidentical hematopoietic stem cell transplantation (HSCT) and is currently in complete remission. The goal of this review is to gain insight into the various hematological diseases associated with NS, starting from our unique case. Full article

Pro-B- and pre-B-cells are consecutive entities in early B-cell development, representing cells of origin for B-cell precursor acute lymphoid leukemia (BCP-ALL). Normal B-cell differentiation is critically regulated by specific transcription factors (TFs). Accordingly, TF-encoding genes are frequently deregulated or mutated in BCP-ALL. Recently, we described TF-codes which delineate physiological activities of selected groups of TF-encoding genes in hematopoiesis including B-cell development. Here, we exploited these codes to uncover regulatory connections between particular TFs in pro-B- and pre-B-cells via an analysis of developmental TFs encoded by NKL and TALE homeobox genes and by ETS and T-box genes. Comprehensive expression analyses in BCP-ALL cell lines helped identify validated models to study their mutual regulation in vitro. Knockdown and overexpression experiments and subsequent RNA quantification of TF-encoding genes in selected model cell lines revealed activating, inhibitory or absent connections between nine TFs operating in early B-cell development, including HLX, MSX1, IRX1, MEIS1, ETS2, ERG, SPIB, EOMES, and TBX21. In addition, genomic profiling revealed BCP-ALL subtype-specific copy number alterations of ERG at 21q22, while a deletion of the TGFbeta-receptor gene TGFBR2 at 3p24 resulted in an upregulation of EOMES. Finally, we combined the data to uncover gene regulatory networks which control normal differentiation of early B-cells, collectively endorsing more detailed evaluation of BCP-ALL subtypes. Full article

Detection of minimal residual disease (MRD) is a major independent prognostic marker in the clinical management of pediatric and adult B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL), and risk stratification nowadays heavily relies on MRD diagnostics. MRD can be detected using flow cytometry based on aberrant expression of markers (antigens) during malignant B-cell maturation. Recent advances highlight the significance of novel markers (e.g., CD58, CD81, CD304, CD73, CD66c, and CD123), improving MRD identification. Second and next-generation flow cytometry, such as the EuroFlow consortium’s eight-color protocol, can achieve sensitivities down to 10⁻⁵ (comparable with the PCR-based method) if sufficient cells are acquired. The introduction of targeted therapies (especially those targeting CD19, such as blinatumomab or CAR-T19) introduces several challenges for flow cytometric MRD analysis, such as the occurrence of CD19-negative relapses. Therefore, innovative flow cytometry panels, including alternative B-cell markers (e.g., CD22 and CD24), have been designed. (Semi-)automated MRD assessment, employing machine learning algorithms and clustering tools, shows promise but does not yet allow robust and sensitive automated analysis of MRD. Future directions involve integrating artificial intelligence, further automation, and exploring multicolor spectral flow cytometry to standardize MRD assessment and enhance diagnostic and prognostic robustness of MRD diagnostics in BCP-ALL. Full article

Acute lymphoblastic leukaemia (ALL) is the most prevalent cancer in children, and excessive iron buildup resulting from blood transfusions and chemotherapy potentially has a negative impact on treatment outcomes and prognosis in patients with ALL. Therefore, initiating early iron chelation therapy during ALL treatment is a logical approach. Ideally, the selected iron chelator should also possess anti-leukaemia properties. The aim of the present study was to explore the potential impact and underlying mechanism of deferasirox (DFX) in ALL therapy. This study proved that DFX, an iron chelator, is capable of inducing leukaemia cell death through ferroptosis, which is achievable by increasing the expression of acetylated nuclear factor erythroid 2-related factor 2 (NRF2). More specifically, NRF2 acetylation on Lys599 was facilitated by acetyltransferase-p300/CBP. These findings indicate that DFX could serve as a potent adjunctive medication for patients with ALL. Moreover, DFX may offer dual benefits in ALL treatment, functioning as both an iron chelator and NRF2-modulating agent. Further research and clinical trials are necessary to fully elucidate the therapeutic potential of DFX in patients with ALL and incorporate it into treatment protocols. Full article

Next-generation sequencing (NGS) methods have been introduced for immunoglobulin (IG)/T-cell receptor (TR) gene rearrangement analysis in acute lymphoblastic leukemia (ALL) and lymphoma (LBL). These methods likely constitute faster and more sensitive approaches to analyze heterogenous cases of ALL/LBL, yet it is not known whether gene rearrangements constituting low percentages of the total sequence reads represent minor subpopulations of malignant cells or background IG/TR gene rearrangements in normal B-and T-cells. In a comparison of eight cases of B-cell precursor ALL (BCP-ALL) using both the EuroClonality NGS method and the IdentiClone multiplex-PCR/gene-scanning method, the NGS method identified between 29% and 139% more markers than the gene-scanning method, depending on whether the NGS data analysis used a threshold of 5% or 1%, respectively. As an alternative to using low thresholds, we show that IG/TR gene rearrangements in subpopulations of cancer cells can be discriminated from background IG/TR gene rearrangements in normal B-and T-cells through a combination of flow cytometry cell sorting and multiple displacement amplification (MDA)-based whole genome amplification (WGA) prior to the NGS. Using this approach to investigate the clonal evolution in a BCP-ALL patient with double relapse, clonal TR rearrangements were found in sorted leukemic cells at the time of second relapse that could be identified at the time of diagnosis, below 1% of the total sequence reads. These data emphasize that caution should be exerted when interpreting rare sequences in NGS experiments and show the advantage of employing the flow sorting of malignant cell populations in NGS clonality assessments. Full article

The multi-kinase inhibitor dasatinib has been implicated to be effective in pre-B-cell receptor (pre-BCR)-positive acute lymphoblastic leukemia (ALL) expressing the E2A-PBX1 fusion oncoprotein. The TGFβ signaling pathway is involved in a wide variety of cellular processes, including embryonic development and cell homeostasis, and it can have dual roles in cancer: suppressing tumor growth at early stages and mediating tumor progression at later stages. In this study, we identified the upregulation of the TGFβ signaling pathway in our previously generated human dasatinib-resistant pre-BCR⁺/E2A-PBX1⁺ ALL cells using global transcriptomic analysis. We confirm the upregulation of the TGFβ pathway member SMAD3 at the transcriptional and translational levels in dasatinib-resistant pre-BCR⁺/E2A-PBX1⁺ ALL cells. Hence, dasatinib blocks, at least partially, TGFβ-induced SMAD3 phosphorylation in several B-cell precursor (BCP) ALL cell lines as well as in dasatinib-resistant pre-BCR⁺/E2A-PBX1⁺ ALL cells. Activation of the TGFβ signaling pathway by TGF-β1 leads to growth inhibition by cell cycle arrest at the G0/G1 stage, increase in apoptosis and transcriptional changes of SMAD-targeted genes, e.g. c-MYC downregulation, in pre-BCR+/E2A-PBX1+ ALL cells. These results provide a better understanding about the role that the TGFβ signaling pathway plays in leukemogenesis of BCP-ALL as well as in secondary drug resistance to dasatinib. Full article

Acute lymphoblastic leukemia (ALL) is a hematological disease characterized by the dysfunction of the hematopoietic system that leads to arrest at a specific stage of stem cells development, suppressing the average production of cellular hematologic components. BCP-ALL is a neoplasm of the B-cell lineage progenitor. BCP-ALL is caused and perpetuated by several mechanisms that provide the disease with its tumor potential and genetic and cytological characteristics. These pathological features are used for diagnosis and the prognostication of BCP-ALL. However, most of these paraclinical tools can only be obtained by bone marrow aspiration, which, as it is an invasive study, can delay the diagnosis and follow-up of the disease, in addition to the anesthetic risk it entails for pediatric patients. For this reason, it is crucial to find noninvasive and accessible ways to supply information concerning diagnosis, prognosis, and the monitoring of the disease, such as circulating biomarkers. In oncology, a biomarker is any measurable indicator that demonstrates the presence of malignancy, tumoral behavior, prognosis, or responses to treatments. This review summarizes circulating molecules associated with BCP-ALL with potential diagnostic value, classificatory capacity during monitoring specific clinic features of the disease, and/or capacity to identify each BCP-ALL stage regarding its evolution and outcome of the patients with BCP-ALL. In the same way, we provide and classify biomarkers that may be used in further studies focused on clinical approaches or therapeutic target identification for BCP-ALL. Full article

Increased glycolytic metabolism plays an important role in B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL). We previously showed that IGFBP7 exerts mitogenic and prosuvival effects in ALL by promoting IGF1 receptor (IGF1R) permanence on the cell surface, thus prolonging Akt activation upon IGFs/insulin stimulation. Here, we show that sustained activation of the IGF1R–PI3K–Akt axis concurs with GLUT1 upregulation, which enhances energy metabolism and increases glycolytic metabolism in BCP-ALL. IGFBP7 neutralization with a monoclonal antibody or the pharmacological inhibition of the PI3K–Akt pathway was shown to abrogate this effect, restoring the physiological levels of GLUT1 on the cell surface. The metabolic effect described here may offer an additional mechanistic explanation for the strong negative impact seen in ALL cells in vitro and in vivo after the knockdown or antibody neutralization of IGFBP7, while reinforcing the notion that it is a valid target for future therapeutic interventions. Full article

Next-generation sequencing technology has improved molecular genetic analysis, and many molecular genetic studies have been utilized for diagnostic classification, risk stratification, and prognosis prediction of acute lymphoblastic leukemia (ALL). Inactivation of neurofibromin or Nf1, a protein derived from the NF1 gene, causes Ras pathway regulation failure, which is related to leukemogenesis. Pathogenic variants of the NF1 gene in B-cell lineage ALL are uncommon, and in this study, we reported a pathogenic variant that is not registered in any public database. The patient diagnosed with B-cell lineage ALL had no clinical symptoms of neurofibromatosis. Studies on the biology, diagnosis, and treatment of this uncommon disease, as well as other related hematologic neoplasms, such as acute myeloid leukemia and juvenile myelomonocytic leukemia, were reviewed. Biological studies included epidemiological differences among age intervals and pathways for leukemia, such as the Ras pathway. Diagnostic studies included cytogenetic, FISH, and molecular tests for leukemia-related genes and ALL classification, such as Ph-like ALL or BCR-ABL1-like ALL. Treatment studies included pathway inhibitors and chimeric antigen cell receptor T-cells. Resistance mechanisms related to leukemia drugs were also investigated. We believe that these literature reviews will enhance medical care for the uncommon diagnosis of B-cell lineage ALL. Full article

IRX genes are members of the TALE homeobox gene class and encode six related transcription factors (IRX1–IRX6) controlling development and cell differentiation of several tissues in humans. Classification of TALE homeobox gene expression patterns for the hematopoietic compartment, termed TALE-code, has revealed exclusive IRX1 activity in pro-B-cells and megakaryocyte erythroid progenitors (MEPs), highlighting its specific contribution to developmental processes at these early stages of hematopoietic lineage differentiation. Moreover, aberrant expression of IRX homeobox genes IRX1, IRX2, IRX3 and IRX5 has been detected in hematopoietic malignancies, including B-cell precursor acute lymphoblastic leukemia (BCP-ALL), T-cell ALL, and some subtypes of acute myeloid leukemia (AML). Expression analyses of patient samples and experimental studies using cell lines and mouse models have revealed oncogenic functions in cell differentiation arrest and upstream and downstream genes, thus, revealing normal and aberrant regulatory networks. These studies have shown how IRX genes play key roles in the development of both normal blood and immune cells, and hematopoietic malignancies. Understanding their biology serves to illuminate developmental gene regulation in the hematopoietic compartment, and may improve diagnostic classification of leukemias in the clinic and reveal new therapeutic targets and strategies. Full article

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a frequent type of childhood hematological malignancy. The disease is classified into several subtypes according to genetic abnormalities. MicroRNAs (miRNAs) are involved in pathological processes (e.g., proliferation, apoptosis, differentiation). A miRNA is a group of short non-coding RNAs with relevant regulatory effects on gene expression achieved by suppression of the translation or degradation of messenger RNA (mRNA). These molecules act as tumor suppressors and/or oncogenes in the pathogenesis of pediatric leukemias. The characteristic features of miRNAs are their stable form and the possibility of secretion to the circulatory system. The role of miRNA in BCP-ALL pathogenesis is still emerging, but several studies have suggested using miRNA expression profiles as biomarkers for diagnosis, prognosis, and response to therapy in leukemia. The dysregulation of some miRNAs involved in childhood acute lymphoid leukemia, such as miR-155, miR-200c, miR-100, miR-181a, miR125b, and miR146a is discussed, showing their possible employment as therapeutic targets. In the current review, the capabilities of miRNAs in non-invasive diagnostics and their prognostic potential as biomarkers are presented. Full article

Acute lymphoblastic leukemias arising from the malignant transformation of B-cell precursors (BCP-ALLs) are protected against chemotherapy by both intrinsic factors as well as by interactions with bone marrow stromal cells. Galectin-1 and Galectin-3 are lectins with overlapping specificity for binding polyLacNAc glycans. Both are expressed by bone marrow stromal cells and by hematopoietic cells but show different patterns of expression, with Galectin-3 dynamically regulated by extrinsic factors such as chemotherapy. In a comparison of Galectin-1 x Galectin-3 double null mutant to wild-type murine BCP-ALL cells, we found reduced migration, inhibition of proliferation, and increased sensitivity to drug treatment in the double knockout cells. Plant-derived carbohydrates GM-CT-01 and GR-MD-02 were used to inhibit extracellular Galectin-1/-3 binding to BCP-ALL cells in co-culture with stromal cells. Treatment with these compounds attenuated migration of the BCP-ALL cells to stromal cells and sensitized human BCP-ALL cells to vincristine and the targeted tyrosine kinase inhibitor nilotinib. Because N-glycan sialylation catalyzed by the enzyme ST6Gal1 can regulate Galectin cell-surface binding, we also compared the ability of BCP-ALL wild-type and ST6Gal1 knockdown cells to resist vincristine treatment when they were co-cultured with Galectin-1 or Galectin-3 knockout stromal cells. Consistent with previous results, stromal Galectin-3 was important for maintaining BCP-ALL fitness during chemotherapy exposure. In contrast, stromal Galectin-1 did not significantly contribute to drug resistance, and there was no clear effect of ST6Gal1-catalysed N-glycan sialylation. Taken together, our results indicate a complicated joint contribution of Galectin-1 and Galectin-3 to BCP-ALL survival, with different roles for endogenous and stromal produced Galectins. These data indicate it will be important to efficiently block both extracellular and intracellular Galectin-1 and Galectin-3 with the goal of reducing BCP-ALL persistence in the protective bone marrow niche during chemotherapy. Full article