Dysregulated arginine metabolism in precursor B-cell acute lymphoblastic leukemia in children: a metabolomic study
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ABSTRACT:
SUBMITTER: Wang W
PROVIDER: S-EPMC11340190 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC9856444 | biostudies-literature
Project description:In childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), cytogenetic abnormalities remain important diagnostic and prognostic tools. A number of well-established abnormalities are routinely used in risk stratification for treatment. These include high hyperdiploidy and ETV6-RUNX1 fusion, classified as good risk, while Philadelphia chromosome (Ph) positive ALL and rearrangements of the KMT2A (MLL) gene define poor risk. A poor risk subgroup of intrachromosomal amplification of chromosome 21 (iAMP21-ALL) has been described, in which intensification of therapy has greatly improved outcome. Until recently, no consistent molecular features were defined in around 30% of BCP-ALL (known as B-other-ALL). Recent studies are classifying them into distinct subgroups, some with clear potential for novel therapeutic approaches. For example, in 1 poor risk subtype, known as Ph-like/BCR-ABL1-like ALL, approximately 10% have rearrangements of ABL-class tyrosine kinases: including ABL1, ABL2, PDGFRB, PDGFRA, and CSF1R. Notably, they show a poor response to standard chemotherapy, while they respond to treatment with tyrosine kinase inhibitors, such as imatinib. In other Ph-like-ALL patients, deregulation of the cytokine receptor, CRLF2, and JAK2 rearrangements lead to activation of the JAK-STAT signaling pathway, implicating a specific role for JAK inhibitors in their treatment. Other novel subgroups within B-other-ALL are defined by the IGH-DUX4 translocation, related to deletions of the ERG gene and a good outcome, while fusions involving ZNF384, MEF2D, and intragenic PAX5 amplification (PAX5 AMP) are linked to a poor outcome. Continued genetic screening will eventually lead to complete genomic classification of BCP-ALL and define more molecular targets for less toxic therapies.
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Project description:B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be classified into subtypes according to the genetic aberrations they display. For instance, the translocation t(12;21)(p13;q22), representing the ETV6-RUNX1 fusion gene (ER), is present in a quarter of BCP-ALL cases. However, around 10% of the cases lack classifying chromosomal abnormalities (B-other). In pediatric ER BCP-ALL, rearrangement mediated by RAG (recombination-activating genes) has been proposed as the predominant driver of oncogenic rearrangement. Herein we analyzed almost 1600 pediatric BCP-ALL samples to determine which subtypes express RAG. We demonstrate that RAG1 mRNA levels are especially high in the ETV6-RUNX1 (ER) subtype and in a subset of B-other samples. We also define 31 genes that are co-expressed with RAG1 (RAG1-signature) in the ER subtype, a signature that also identifies this subset of B-other samples. Moreover, this subset also shares leukemia and pro-B gene expression signatures as well as high levels of the ETV6 target genes (BIRC7, WBP1L, CLIC5, ANGPTL2) with the ER subtype, indicating that these B-other cases are the recently identified ER-like subtype. We validated our results in a cohort where ER-like has been defined, which confirmed expression of the RAG1-signature in this recently described subtype. Taken together, our results demonstrate that the RAG1-signature identifies the ER-like subtype. As there are no definitive genetic markers to identify this novel subtype, the RAG1-signature represents a means to screen for this leukemia in children.
| S-EPMC8209579 | biostudies-literature
Project description:Here, we report the results of the prospective cohort study EORTC-CLG 58081 and compare them to the control arm of the randomized phase 3 trial EORTC-CLG 58951, on which treatment recommendations were built. In both studies, patients aged 1-18 years with BCR::ABL1 negative acute lymphoblastic leukemia of the B-lineage (B-ALL) or T-lineage (T-ALL) were treated using a BFM backbone without cranial irradiation. Similarly to the control arm of 58951, prednisolone (PRED) 60 mg/m2/day was used for induction therapy, but a few modifications were made. Dexamethasone (DXM) was used in average-risk 2 (AR2) T-ALL and B-ALL during induction, 10 and 6 mg/m2/day, respectively. Leucovorin rescue was delayed to 42 h instead of 36 h after initiation of high-dose methotrexate, and a postconsolidation MRD time point was added to stratify patients. Between 2011 and 2017, 835 patients were prospectively enrolled in the 58081 study. Overall, the 5-year event-free survival (EFS) was 84.8% versus 83.6% (hazard ratio [HR], 0.96 [95% confidence interval [CI]: 0.76-1.21]) for 58081 versus 58951 considered as a control group, respectively, 84.3% versus 84.9% (HR, 1.06 [99% CI: 0.75-1.49]) in B-ALL but 87.3% versus 76.6% (HR, 0.59 [99% CI: 0.28-1.24]) in T-ALL. The comparison between the two studies regarding EFS differed by risk group (p = 0.012). The HR was 2.15 (99% CI: 0.67-6.85) for very low-risk but 0.34 (99% CI: 0.13-0.89) for AR2. The particularly favorable results observed in the T-ALLs and AR2 subgroups suggest the benefit of using DXM in specific patient groups and highlight the importance of risk stratification.
| S-EPMC11558101 | biostudies-literature
Project description:B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed-lineage leukemia gene rearrangement (MLL-r) is a poor-prognosis subtype for which additional therapeutic targets are urgently needed. Currently no multi-omics data set for primary MLL r patient cells exists that integrates transcriptomics, proteomics and glycomics to gain an inclusive picture of theranostic targets. Methods: We have integrated transcriptomics, proteomics and glycomics to i) obtain the first inclusive picture of primary patient BCP-ALL cells and identify molecular signatures that distinguish leukemic from normal precursor B-cells and ii) better understand the benefits and limitations of the applied technologies to deliver deep molecular sequence data across major cellular biopolymers. Results: MLL-r cells feature an extensive remodeling of their glycocalyx, with increased levels of Core 2-type O-glycans and complex N-glycans as well as significant changes in sialylation and fucosylation. Notably, glycosaminoglycan remodeling from chondroitin sulfate to heparan sulfate was observed. A survival screen, to determine if glycan remodeling enzymes are redundant, identified MGAT1 and NGLY1, essential components of the N-glycosylation/degradation pathway, as highly relevant within this in vitro screening. OGT and OGA, unique enzymes that regulate intracellular O-GlcNAcylation, were also indispensable. Transcriptomics and proteomics further identified Fes and GALNT7-mediated glycosylation as possible therapeutic targets. While there is overall good correlation between transcriptomics and proteomics data, we demonstrate that a systematic combined multi-omics approach delivers important diagnostic information that is missed when applying a single omics technology. Conclusions: Apart from confirming well-known MLL-r BCP-ALL glycoprotein markers, our integrated multi-omics workflow discovered previously unidentified diagnostic/therapeutic protein targets.
| S-EPMC8490503 | biostudies-literature
Project description:The prognosis for adults with precursor B-cell acute lymphoblastic leukemia (B-ALL) remains poor, in part from a lack of therapeutic targets. We identified the type I cytokine receptor subunit CRLF2 in a functional screen for B-ALL-derived mRNA transcripts that can substitute for IL3 signaling. We demonstrate that CRLF2 is overexpressed in approximately 15% of adult and high-risk pediatric B-ALL that lack MLL, TCF3, TEL, and BCR/ABL rearrangements, but not in B-ALL with these rearrangements or other lymphoid malignancies. CRLF2 overexpression can result from translocation with the IGH locus or intrachromosomal deletion and is associated with poor outcome. CRLF2 overexpressing B-ALLs share a transcriptional signature that significantly overlaps with a BCR/ABL signature, and is enriched for genes involved in cytokine receptor and JAK-STAT signaling. In a subset of cases, CRLF2 harbors a Phe232Cys gain-of-function mutation that promotes constitutive dimerization and cytokine independent growth. A mutually exclusive subset harbors activating mutations in JAK2. In fact, all 22 B-ALLs with mutant JAK2 that we analyzed overexpress CRLF2, distinguishing CRLF2 as the key scaffold for mutant JAK2 signaling in B-ALL. Expression of WT CRLF2 with mutant JAK2 also promotes cytokine independent growth that, unlike CRLF2 Phe232Cys or ligand-induced signaling by WT CRLF2, is accompanied by JAK2 phosphorylation. Finally, cells dependent on CRLF2 signaling are sensitive to small molecule inhibitors of either JAKs or protein kinase C family kinases. Together, these findings implicate CRLF2 as an important factor in B-ALL with diagnostic, prognostic, and therapeutic implications.
| S-EPMC2806782 | biostudies-literature
Project description:MicroRNAs (miRNAs) play dual roles in acute lymphoblastic leukemia (ALL) as both tumor suppressors and oncogenes, and miRNA expression profiles can be used for patient risk stratification. Precise assessment of miRNA levels is crucial for understanding their role and function in gene regulation. Quantitative real-time polymerase chain reaction (qPCR) is a reliable, rapid, and cost-effective method for analyzing miRNA expression, assuming that appropriate normalization to stable references is performed to ensure valid data. In this study, we evaluated the stability of six commonly used miRNA references (5sRNA, SNORD44, RNU6, RNU1A1, miR-103a-3p, and miR-532-5p) across nine B-cell precursor (BCP) ALL cell lines, 22 patient-derived xenograft (PDX) BCP ALL samples from different organ compartments of leukemia bearing mice, and peripheral blood mononuclear cells (PBMCs) from six healthy donors. We used four different algorithms (Normfinder, ∆CT, geNorm, and BestKeeper) to assess the most stably expressed reference across all samples. Moreover, we validated our data in an additional set of 13 PDX ALL samples and six healthy controls, identifying miR-103a-3p and miR-532-5p as the most stable references for miRNA normalization in BCP ALL studies. Additionally, we demonstrated the critical importance of using a stable reference to accurately interpret miRNA data.
| S-EPMC11531470 | biostudies-literature
Project description:IntroductionThe prognostic role of Wilms' tumor 1 (WT1) gene expression at diagnosis in children with B cell precursor acute lymphoblastic leukemia (BCP-ALL) is still controversial.MethodsWe detected the WT1 transcript levels of 533 de novo pediatric BCP-ALL patients using TaqMan-based real-time quantitative PCR and analyzed their clinical features.ResultsThe WT1 transcript levels differed among the distinct molecularly defined groups, with the highest levels in the KMT2A rearrangements (KMT2A-r) group. According to the results of the X-tile software, all patients were divided into two groups: WT1/ABL ≥ 0.24% (group A) and <0.24% (group B). The proportions of patients whose age was ≥10 years old, with immunophenotype of Pro-B, belonging in high-risk group, or with minimal residual disease (MRD) ≥ 0.01% at week 12 were significantly higher in group A than in group B. In the B-other group, WT1 overexpression was an independent risk factor of overall survival (OS) rate (P = 0.042), and higher MRD ≥ 0.01% at week 12 was associated with lower OS rate (P<0.001) and event-free survival rate (P<0.001). Moreover, the subgroup analysis revealed that, in patients with initial WBC<50 × 109/L or MRD<0.1% at day 33 or MRD<0.01% at week 12 or in the standard-risk group, WT1 overexpression led to a poorer outcome in comparison with those with WT1 downexpression (P<0.05).DiscussionTherefore, pediatric BCP-ALL with WT1 overexpression had unique clinico-pathological characteristics and poor treatment response. In B-other patients, WT1 overexpression at diagnosis predicted an inferior prognosis. The WT1 gene may serve as a biomarker for monitoring residual disease in the B-other population, especially in children in the standard-risk group.
| S-EPMC10825953 | biostudies-literature
Project description:Background/Objectives: Relapsed B-cell acute lymphoblastic leukemia (B-ALL) remains an unresolved matter of concern regarding adverse outcomes. This case study aimed to evaluate the effectiveness of blinatumomab, with or without door lymphocyte infusion (DLI), in treating measurable residual disease (MRD)-positive B-ALL. Methods: All patients who received blinatumomab salvage therapy were included in this study. Eleven patients were included in the study. All patients were evaluated for MRD-negativity. Results: Before starting blinatumomab therapy, seven patients tested positive for MRD, three tested negative, and one had refractory disease. Hematopoietic cell transplantation (HCT) was reserved for five patients with persistent MRD. Six patients became MRD-negative and subsequent HCT was not performed. Only two patients relapsed; one patient died of relapse, and the other one received carfilzomib-based therapy and was MRD-negative thereafter. Nine patients were MRD-negative at a median follow-up of 28 months (15-52 months). Two of three MRD-positive post-transplant patients remained in complete molecular remission after preemptive DLI at the last follow-up date. In the first salvage, blinatumomab may achieve complete remission and bridging to HCT in pediatric patients with end-of-induction MRD-positive B-cell precursor ALL. Conclusions: The decision on how to treat post-transplant relapse continues to affect survival outcomes. Blinatumomab combined with DLI may extend the armamentarium of release options for high-risk pediatric patients. This approach is encouraging for high-risk ALL patients who are MRD-positive post-transplantation.
| S-EPMC11204057 | biostudies-literature
Project description:Early precursor T cell-acute lymphoblastic leukemia (ETP-ALL) is a rare entity characterized by chemo-resistance and a paucity of data regarding optimal management. We review here the literature regarding the management of ETP-ALL and focus on the recent, emerging data, regarding the potential role of molecularly targeted approaches with a focus on venetoclax.
| S-EPMC7370557 | biostudies-literature