Dataset Information

Identification and characterization of a murine model of BCR?ABL1+ acute B?lymphoblastic leukemia with central nervous system metastasis.

ABSTRACT: Breakpoint cluster region (BCR)?Abelson murine leukemia (ABL)1+ acute B?lymphoblastic leukemia (B?ALL) is a disease associated with a dismal prognosis and a high incidence of central nervous system (CNS) metastasis. However, BCR?ABL1+ B?ALL with CNS infiltration has not been previously characterized, at least to the best of our knowledge. In the present study, a murine model of BCR?ABL1+ B?ALL with CNS metastasis was established using retroviral transduction. The vast majority of BCR?ABL1+ leukemic cells were found to be immature B cells with a variable proportion of pro?B and pre?B populations. The present results indicated that the BCR?ABL1+ B?leukemic cells expressed high levels integrin subunit alpha 6 (Itga6) and L?selectin adhesion molecules, and have an intrinsic ability to disseminate and accumulate in CNS tissues, predominantly in meninges. On the whole, these results provide an approach for addressing the mechanisms of BCR?ABL1+ B?ALL with CNS metastasis and may guide the development of novel therapeutic strategies.

SUBMITTER: Yu X

PROVIDER: S-EPMC6610040 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Identification and characterization of a murine model of BCR‑ABL1+ acute B‑lymphoblastic leukemia with central nervous system metastasis.

Yu Xiaozhuo X Zhang Hua H Yuan Meng M Zhang Ping P Wang Yang Y Zheng Mingzhe M Lv Zhuangwei Z Odhiambo Woodvine Otieno WO Li Canyu C Liu Chengcheng C Ma Yunfeng Y Ji Yanhong Y

Oncology reports 20190603 2

Breakpoint cluster region (BCR)‑Abelson murine leukemia (ABL)1+ acute B‑lymphoblastic leukemia (B‑ALL) is a disease associated with a dismal prognosis and a high incidence of central nervous system (CNS) metastasis. However, BCR‑ABL1+ B‑ALL with CNS infiltration has not been previously characterized, at least to the best of our knowledge. In the present study, a murine model of BCR‑ABL1+ B‑ALL with CNS metastasis was established using retroviral transduction. The vast majority of BCR‑ABL1+ leuke ...[more]

PMID: 31173268

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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.

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.

Dataset Information

Identification and characterization of a murine model of BCR?ABL1+ acute B?lymphoblastic leukemia with central nervous system metastasis.

Publications

Identification and characterization of a murine model of BCR‑ABL1+ acute B‑lymphoblastic leukemia with central nervous system metastasis.

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