Acute lymphoblastic leukemia of the central nervous system: on the role of PBX1.
Ontology highlight
ABSTRACT:
SUBMITTER: Alsadeq A
PROVIDER: S-EPMC5395101 | biostudies-literature | 2017 Apr
REPOSITORIES: biostudies-literature
Publications
Acute lymphoblastic leukemia of the central nervous system: on the role of PBX1.
Alsadeq Ameera A Schewe Denis M DM
Haematologica 20170401 4
Similar Datasets
Project description:Central nervous system acute lymphoblastic leukemia (CNS-ALL) is a major clinical problem. Prophylactic therapy is neurotoxic, and a third of the relapses involve the CNS. Increased expression of interleukin 15 (IL-15) in leukemic blasts is associated with increased risk for CNS-ALL. Using in vivo models for CNS leukemia caused by mouse T-ALL and human xenografts of ALL cells, we demonstrate that expression of IL-15 in leukemic cells is associated with the activation of natural killer (NK) cells. This activation limits the outgrowth of leukemic cells in the periphery, but less in the CNS because NK cells are excluded from the CNS. Depletion of NK cells in NOD/SCID mice enabled combined systemic and CNS leukemia of human pre-B-ALL. The killing of human leukemia lymphoblasts by NK cells depended on the expression of the NKG2D receptor. Analysis of bone marrow (BM) diagnostic samples derived from children with subsequent CNS-ALL revealed a significantly high expression of the NKG2D and NKp44 receptors. We suggest that the CNS may be an immunologic sanctuary protected from NK-cell activity. CNS prophylactic therapy may thus be needed with emerging NK cell-based therapies against hematopoietic malignancies.
| S-EPMC7265786 | biostudies-literature
Project description:Central nervous system infiltration and relapse are poorly understood in childhood acute lymphoblastic leukemia. We examined the role of zeta-chain-associated protein kinase 70 in preclinical models of central nervous system leukemia and performed correlative studies in patients. Zeta-chain-associated protein kinase 70 expression in acute lymphoblastic leukemia cells was modulated using short hairpin ribonucleic acid-mediated knockdown or ectopic expression. We show that zeta-chain-associated protein kinase 70 regulates CCR7/CXCR4 via activation of extracellular signal-regulated kinases. High expression of zeta-chain-associated protein kinase 70 in acute lymphoblastic leukemia cells resulted in a higher proportion of central nervous system leukemia in xenografts as compared to zeta-chain-associated protein kinase 70 low expressing counterparts. High zeta-chain-associated protein kinase 70 also enhanced the migration potential towards CCL19/CXCL12 gradients in vitro CCR7 blockade almost abrogated homing of acute lymphoblastic leukemia cells to the central nervous system in xenografts. In 130 B-cell precursor acute lymphoblastic leukemia and 117 T-cell acute lymphoblastic leukemia patients, zeta-chain-associated protein kinase 70 and CCR7/CXCR4 expression levels were significantly correlated. Zeta-chain-associated protein kinase 70 expression correlated with central nervous system disease in B-cell precursor acute lymphoblastic leukemia, and CCR7/CXCR4 correlated with central nervous system involvement in T-cell acute lymphoblastic leukemia patients. In multivariate analysis, zeta-chain-associated protein kinase 70 expression levels in the upper third and fourth quartiles were associated with central nervous system involvement in B-cell precursor acute lymphoblastic leukemia (odds ratio=7.48, 95% confidence interval, 2.06-27.17; odds ratio=6.86, 95% confidence interval, 1.86-25.26, respectively). CCR7 expression in the upper fourth quartile correlated with central nervous system positivity in T-cell acute lymphoblastic leukemia (odds ratio=11.00, 95% confidence interval, 2.00-60.62). We propose zeta-chain-associated protein kinase 70, CCR7 and CXCR4 as markers of central nervous system infiltration in acute lymphoblastic leukemia warranting prospective investigation.
| S-EPMC5286942 | biostudies-literature
Project description:Delivery of effective anti-leukemic agents to the central nervous system (CNS) is considered essential for cure of childhood acute lymphoblastic leukemia. Current CNS-directed therapy comprises systemic therapy with good CNS-penetration accompanied by repeated intrathecal treatments up to 26 times over 2-3 years. This approach prevents most CNS relapses, but is associated with significant short and long term neurotoxicity. Despite this burdensome therapy, there have been no new drugs licensed for CNS-leukemia since the 1960s, when very limited anti-leukemic agents were available and there was no mechanistic understanding of leukemia survival in the CNS. Another major barrier to improved treatment is that we cannot accurately identify children at risk of CNS relapse, or monitor response to treatment, due to a lack of sensitive biomarkers. A paradigm shift in treating the CNS is needed. The challenges are clear - we cannot measure CNS leukemic load, trials have been unable to establish the most effective CNS treatment regimens, and non-toxic approaches for relapsed, refractory, or intolerant patients are lacking. In this review we discuss these challenges and highlight research advances aiming to provide solutions. Unlocking the potential of risk-adapted non-toxic CNS-directed therapy requires; (1) discovery of robust diagnostic, prognostic and response biomarkers for CNS-leukemia, (2) identification of novel therapeutic targets combined with associated investment in drug development and early-phase trials and (3) engineering of immunotherapies to overcome the unique challenges of the CNS microenvironment. Fortunately, research into CNS-ALL is now making progress in addressing these unmet needs: biomarkers, such as CSF-flow cytometry, are now being tested in prospective trials, novel drugs are being tested in Phase I/II trials, and immunotherapies are increasingly available to patients with CNS relapses. The future is hopeful for improved management of the CNS over the next decade.
| S-EPMC9712093 | biostudies-literature
Project description:Treatment of the central nervous system (CNS) is an essential therapeutic component in childhood acute lymphoblastic leukemia (ALL). The goal of this study was to identify molecular signatures distinguishing patients with CNS disease from those without the disease in pediatric patients with ALL. We analyzed gene expression data from 207 pediatric patients with ALL. Patients without CNS were classified as CNS1, while those with mild and advanced CNS disease were classified as CNS2 and CNS3, respectively. We compared gene expression levels among the three disease classes. We identified gene signatures distinguishing the three disease classes. Pathway analysis revealed molecular networks and biological pathways dysregulated in response to CNS disease involvement. The identified pathways included the ILK, WNT, B-cell receptor, AMPK, ERK5, and JAK signaling pathways. The results demonstrate that transcription profiling could be used to stratify patients to guide therapeutic decision-making in pediatric ALL.
| S-EPMC4792199 | biostudies-literature
Project description:Background In childhood acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is rare at diagnosis (1-4%), but more frequent at relapse (~30%). Minimal residual disease diagnostics predict most bone marrow (BM) relapses, but likely cannot predict isolated CNS relapses. Consequently, CNS relapses may become relatively more important. Because of the significant late sequelae of CNS treatment, early identification of patients at risk of CNS relapse is crucial. Methods Gene expression profiles of ALL cells from cerebrospinal fluid (CSF) and ALL cells from BM were compared and differences were confirmed by real-time quantitative PCR. For a selected set of overexpressed genes, protein expression levels of ALL cells in CSF at relapse and of ALL cells in diagnostic BM samples were evaluated by 8-color flow cytometry. Results CSF-derived ALL cells showed a clearly different gene expression profile than BM-derived ALL cells, with differentially-expressed genes (including SCD and OPN) involved in survival and apoptosis pathways and linked to the JAK-STAT pathway. Flowcytometric analysis showed that a subpopulation of ALL cells (>1%) with a â??CNS signatureâ?? (SCD positivity and increased OPN expression) was already present in BM at diagnosis in ALL patients who later developed a CNS relapse, but was <1% or absent in virtually all other patients. Conclusions The presence of a subpopulation of ALL cells with a â??CNS signatureâ?? at diagnosis may predict isolated CNS relapse. Such information can be used to design new diagnostic and treatment strategies that aim at prevention of CNS relapse with reduced toxicity. We compared gene expression profiles of ALL cells obtained from cerebrospinal fluid (n=8) with profiles of ALL cells obtained from bone marrow at diagnosis (n=22) or at relapse (n=20)
2015-12-31 | E-GEOD-60926 | biostudies-arrayexpress
Project description:Background In childhood acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is rare at diagnosis (1-4%), but more frequent at relapse (~30%). Minimal residual disease diagnostics predict most bone marrow (BM) relapses, but likely cannot predict isolated CNS relapses. Consequently, CNS relapses may become relatively more important. Because of the significant late sequelae of CNS treatment, early identification of patients at risk of CNS relapse is crucial. Methods Gene expression profiles of ALL cells from cerebrospinal fluid (CSF) and ALL cells from BM were compared and differences were confirmed by real-time quantitative PCR. For a selected set of overexpressed genes, protein expression levels of ALL cells in CSF at relapse and of ALL cells in diagnostic BM samples were evaluated by 8-color flow cytometry. Results CSF-derived ALL cells showed a clearly different gene expression profile than BM-derived ALL cells, with differentially-expressed genes (including SCD and OPN) involved in survival and apoptosis pathways and linked to the JAK-STAT pathway. Flowcytometric analysis showed that a subpopulation of ALL cells (>1%) with a “CNS signature” (SCD positivity and increased OPN expression) was already present in BM at diagnosis in ALL patients who later developed a CNS relapse, but was <1% or absent in virtually all other patients. Conclusions The presence of a subpopulation of ALL cells with a “CNS signature” at diagnosis may predict isolated CNS relapse. Such information can be used to design new diagnostic and treatment strategies that aim at prevention of CNS relapse with reduced toxicity.
2015-12-31 | GSE60926 | GEO
Project description:The central nervous system (CNS) is the most important site of extramedullary disease in adults with acute lymphoblastic leukemia (ALL). Although CNS disease is identified only in a minority of patients at the time of diagnosis, subsequent CNS relapses (either isolated or concurrent with other sites) occur in some patients even after the delivery of prophylactic therapy targeted to the CNS. Historically, prophylaxis against CNS disease has included intrathecal (IT) chemotherapy and radiotherapy (RT), although the latter is being used with decreasing frequency. Treatment of a CNS relapse usually involves intensive systemic therapy and cranial or craniospinal RT along with IT therapy and consideration of allogeneic hematopoietic cell transplant. However, short- and long-term toxicities can make these interventions prohibitively risky, particularly for older adults. As new antibody-based immunotherapy agents have been approved for relapsed/refractory B-cell ALL, their use specifically for patients with CNS disease is an area of keen interest not only because of the potential for efficacy but also concerns of unique toxicity to the CNS. In this review, we discuss data-driven approaches for these common and challenging clinical scenarios as well as highlight how recent findings potentially support the use of novel immunotherapeutic strategies for CNS disease.
| S-EPMC10082377 | biostudies-literature
Project description:BackgroundAcute lymphoblastic leukemia (ALL) is prone to metastasize to the central nervous system (CNS), which is an important cause of poor treatment outcomes and unfavorable prognosis. However, the pathogenesis of CNS metastasis of ALL cells has not been fully illuminated. Recent reports have shed some light on the correlation between neural mechanisms and ALL CNS metastasis. These progressions prompt us to study the relationship between ALL central nervous system metastasis and neuronal development, exploring potential biomarkers and therapeutic targets of CNS metastasis.Materials and methodsALL central nervous system metastasis- and neuronal development-related differentially expressed genes (DEGs) were identified by analyzing gene expression datasets GSE60926 and GSE13715. Target prediction and network analysis methods were applied to assess protein-protein interaction networks. Gene Ontology (GO) terms and pathway enrichment for DEGs were assessed. Co-expressed differentially expressed genes (co-DEGs) coupled with corresponding predicted microRNAs (miRNAs) were studied as well. Reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry were employed for the validation of key co-DEGs in primary ALL cells. Furthermore, ALL cells were treated with a vascular endothelial growth factor (VEGF) inhibitor to block neuronal development and assess changes in the co-DEGs.ResultsWe identified 216, 208, and 204 DEGs in ALL CNS metastasis specimens and neuronal development samples (GSE60926 and GSE13715). CD2, CD3G, CD3D, and LCK may be implicated in ALL CNS metastasis. LAMB1, MATN3, IGFBP3, LGALS1, and NEUROD1 may be associated with neuronal development. Specifically, four co-DEGs (LGALS1, TMEM71, SHISA2, and S100A11) may link ALL central nervous system metastasis and neuronal development process. The miRNAs for each co-DEG could be potential biomarkers or therapeutic targets for ALL central nervous system metastasis, especially hsa-miR-22-3p, hsa-miR-548t-5p, and hsa-miR-6134. Additionally, four co-DEGs (LGALS1, TMEM71, SHISA2, and S100A11) were validated in CNS-infiltrated ALL cells. The VEGF inhibitor demonstrated a suppressive effect on mRNA and protein expression of key co-DEGs.ConclusionThe bioinformatic survey and key gene validation suggest a possible correlation between ALL CNS metastasis and the neuronal development process. Simulating the neuronal development process might be a possible strategy for CNS metastasis in ALL. LGALS1, TMEM71, SHISA2, and S100A11 genes are promising and novel biomarkers and targets in ALL CNS metastasis.
| S-EPMC10794646 | biostudies-literature
Project description:Gene expression analysis to identify molecular mechanisms that regulate motility and CNS invasiveness of malignant hMYC-ER and hlkT-lymphoblasts
2017-09-29 | GSE62541 | GEO
Project description:Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has a poor prognosis and remains a therapeutic challenge with few recent advances in therapy. Leptomeningeal disease is particularly common in the high risk subgroup of KMT2A-rearranged B-ALL (KMT2A-r B-ALL). Here we performed transcriptional and proteomic profiling of leukemia cells from bone marrow (BM) and CNS-disseminated disease in KMT2A-r B-ALL xenografts. CNS disease exhibited stemness traits and metabolic reprogramming previously associated with chemotherapy resistance. Genes governing mRNA translation were upregulated in CNS samples, a finding confirmed in cohorts of KMT2A-r B-ALL patients with CNS involvement. This upregulation was functionally important for CNS disease as the mRNA translational inhibitor omacetaxine mepesuccinate (OMA) significantly reduced leptomeningeal disease burden in xenografts. Proteomic analysis demonstrated greater abundance of secreted proteins in CNS infiltrating cells including complement component 3 (C3), a known driver of leptomeningeal metastasis in solid tumours, pointing to a convergent mechanism for this route of metastasis in multiple cancers. Pharmacological inhibition of C3a signaling suppressed CNS dissemination, whereas C3a receptor activation increased CNS disease. Overall, our study identifies mRNA translation and a set of secreted proteins as key mediators of CNS dissemination in KMT2A-r B-ALL. Therapeutic targeting of these dependencies represents a novel approach to prevent or treat leptomeningeal disease.
2023-03-11 | PXD022411 | Pride