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• W4362602566 abstract "The outcome of patients with acute lymphoblastic leukemia (ALL) has progressively improved over the years thanks to a more precise diagnostic and prognostic work-up at presentation based on biological and molecular features, to the increasing use of targeted therapies and to a more personalized follow-up and management of patients.1, 2 Nonetheless, refractory/relapsed cases have an aggressive clinical course and a poor prognosis. At a time when the prognostic likelihood of adult ALL is improving, an extramedullary dissemination to the central nervous system (CNS) is becoming an increasing unmet clinical need.1 CNS localization represents a primary cause of treatment failure and mortality among adult ALL patients.1 A sizable proportion of ALL patients develop a CNS dissemination: in about 3%–5% of patients it can be detected already at diagnosis while in 30%–40% of patients it develops during the course of the disease.1 Irrespective of the initial CNS status, all therapeutic schemes include CNS prophylaxis, mostly based on the combined use of systemic and intrathecal chemotherapy.1 The molecular mechanisms underlying a dissemination to the CNS are still poorly understood and molecular markers predicting CNS involvement in patients with adult ALL are currently lacking. These markers would be critical to implement a tailored therapy that could guide a more effective treatment in patients at a higher risk of CNS localization, in order to prevent a CNS relapse, and to limit the degree of CNS prophylaxis in patients with a low risk of CNS involvement. Several studies have investigated the molecular profile of ALL to understand whether the ability to migrate to the CNS is restricted to a subset of leukemic cells or shared by all cells, with controversial conclusions.3, 4 Some studies have documented a generic potential of leukemic cells to induce a CNS dissemination,3 while others have reported that relapse-initiating clones with a CNS-tropism may be present at diagnosis,4 and that ALL cells isolated from CNS relapses compared to bone marrow (BM) relapses could significantly upregulate trafficking/adhesions genes (e.g., SPP1, IL-15, ICAM1, and LGMN) and activate specific pathways that favor ALL to colonize to the CNS niche.5 Thus, the existence (or not) of a specific gene signature associated with the dissemination of ALL to the CNS is still unclear and conclusions from previous studies are, to our knowledge, mainly derived from pre-clinical approaches, without being adequately investigated in primary human samples. This study was aimed at identifying at diagnosis molecular markers potentially associated with an ALL localization to the CNS at any time during the course of the disease. To this end, we analyzed the expression level of genes previously described as associated to the CNS dissemination by a NanoString custom gene panel (NanoString Technologies, Seattle, WA, US) including. We developed an ad hoc designed target gene-panel that included 71 genes (detailed and referenced in Table S1) selected as follows: 20 genes that had been reported as involved in CNS infiltration in ALL pre-clinical models; 17 neural-related genes identified in a previous work by our group as associated to CNS dissemination in blastic plasmacytoid dendritic cell neoplasm, a hematological malignancy with many features in common with ALL; 20 genes differentially expressed in CNS relapses compared to BM relapses, and available in the GSE60926 in silico dataset; 14 genes found up-regulated at diagnosis in CNS-positive versus CNS-negative pediatric ALL cases obtained from the GSE11877 in silico dataset. This ad hoc custom designed panel was then tested on BM or peripheral blood (PB) diagnostic samples from 32 adult B-lineage ALL cases (9 Ph+ and 23 Ph−), separated into two clinical groups: 1) CNS-negative cases, with no CNS dissemination at any time during the course of the disease (n = 11) and; 2) CNS-positive cases (N = 21) with a CNS involvement at the onset of the disease (n = 7) or at relapse (n = 14). For each patient, complete clinical information was available including PB, BM and cerebrospinal fluid (CSF) examination, and magnetic resonance imaging findings (Table S2). All the RNA samples extracted from the above cases passed the quality control and were loaded on the NanoString nCounter System. Raw data were then normalized and analyzed by the software NanoString nCounter nSolver 4.0 with Advanced Analysis Module 2.0 (Supplementary Methods). We performed a gene expression analysis of ALL CNS-positive cases compared to ALL CNS-negative cases. Five genes were found differentially expressed between the two groups: 2 genes - CENPV and E2F8 - were down-regulated and 3 genes - RNF157, LGMN, and RIPOR2-were up-regulated in CNS-positive versus CNS-negative cases (Pval ≤0.01, │Log2 (FC)│≥1) (Figure 1). Among the up-regulated genes, RNF157 codes for a novel E3 ubiquitin-ligase ring finger protein, which plays a critical role in neuronal survival, dendritic growth and cell-cycle progression of tumor cell lines.6 RIPOR2 is a small GTPase RHOA that inhibits T-lymphocyte responses, such as cell adhesion, polarization and migration.7 LGMN, also known as AEP, is a legumain, an asparaginyl endopeptidase concentrated on the cell membranes where it colocalizes with integrins and takes part in antigen processing.8, 9 Cells overexpressing LGMN show an increased migratory activity in vitro and acquire an invasive and metastatic phenotype in vivo.8 A high LGMN expression has been observed in a variety of solid tumors and also in a subset of childhood ALL characterized by the amplification of chromosome 21 (including RUNX1) and a high risk of extra-medullary relapse.9 Of clinical interest, a prodrug strategy incorporating a legumain-cleavable substrate into doxorubicin has been developed and has shown reduced toxicity and effective tumoricidal activity in a murine colon carcinoma model.7 Among the down-regulated genes, CENPV is essential for centromere organization and chromosome alignment and its depletion may cause chromosome imbalance.10 Lastly, E2F8 is a newly discovered member of the E2F transcription factor family, whose lower expression has been associated with a quiescent cellular state.11 Identification of 5 deregulated genes in acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement. The bar chart shows the genes up-regulated (red) and down-regulated (purple), in CNS-positive versus CNS-negative ALL cases. Overall, in adult B-lineage ALL at presentation we could identify a five-gene signature that may confer a greater CNS invasiveness, both at diagnosis and during the course of the disease, and also induce chromosomal instability. In line with these results, the chromosomal instability is a source of genetic variation that can favor tumor adaptation to stressful environments and resistance to cytotoxic drugs, while the acquisition of cell motility is a fundamental prerequisite for migrating to secondary sites. In synthesis, these 5 genes could favor from the onset of the disease the dissemination of ALL cells to the CNS, support their resistance to treatment and consequently their survival in the CNS microenvironment. Taken together, we propose a five-gene signature which may represent an easy and inexpensive tool to predict CNS dissemination in adult B-lineage ALL at any time during the disease and contribute to drive therapeutic decisions and thus potentially improve further patients' outcome. Showing a gene modulation between adult B-ALL cases CNS-positive and CNS-negative. This observation needs to Whether or not this signature might represent a tool to predict CNS dissemination in adult B-lineage ALL at any time during the disease and contribute to drive therapeutic decision, must be validated on larger series of cases, compatibly with the rareness of the disease. We are currently applying this approach to a multicenter cooperative adult ALL protocol opens to enrollment. Maria Rosaria Sapienza, Robin Foà, Stefano A. Pileri conceived the original idea, interpreted the data and wrote the manuscript; Maria Rosaria Sapienza, Sabina Chiaretti, Deborah Cardinali, planned and performed the molecular experiments; Robin Foà, Sabina Chiaretti, Deborah Cardinali, provided patient samples and clinical data; Maria Rosaria Sapienza, Saveria Mazzara, performed the statistical analysis, Roberto Chiarle critically revised the manuscript; Robin Foà and Stefano A. Pileri supervised the research; and all authors read and contributed to the final version of the manuscript. The authors would like to thank the patients for providing samples for the study and making this research possible. This investigation was supported by Associazione Italiana Ricerca sul Cancro (AIRC), Special 5 × 1000 Program Metastases (21198), Milano (Italy) to RFand SAP. Stefano A. Pileri served on a scientific advisory board for Celgene, NanoString, Roche, BeiGene. Sabina Chiaretti advisory board for Amgen, Incyte, AbbVie, Gilead, Robin Foà speaker's bureau for Amgen, Novartis, AstraZeneca, AbbVie, Roberto Chiarle has stock options in Elicio Therapeutics. Associazione Italiana Ricerca sul Cancro (AIRC), Grant/Award Number: 21198. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1002/hon.3136. The data that support the findings of this study are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W4362602566 date "2023-04-05" @default.
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• W4362602566 title "A five‐gene signature may associate with central nervous system dissemination in adult acute lymphoblastic leukemia" @default.
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