Tumor suppressors BTG1 and BTG2 regulate early mouse B-cell development

Tijchon, Esther; Emst, Liesbeth van; Yuniati, Laurensia; Schenau, Dorette van Ingen; Havinga, Jørn; Rouault, Jean‐Pierre; Hoogerbrugge, Peter M.; Leeuwen, Frank N. van; Scheijen, Blanca

doi:10.3324/haematol.2015.139675

Cited by 27 publications

(26 citation statements)

References 15 publications

(13 reference statements)

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“… 99 , 100 Mice deficient for Btg1 show a partial block in B-cell development, which is even more evident in Btg1 −/− ; Btg2 −/− mice. 101 These studies have demonstrated that BTG1, together with BTG2, is required to suppress a T-lineage inappropriate expression program in progenitor B cells. Thus, monoallelic gene deletions of IKZF1 in combination with EBF1 , PAX5 or BTG1 may contribute to a more prominent block in B-cell development and increased proliferative expansion of precursor B cells.…”

Section: Introductionmentioning

confidence: 99%

The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia

2018

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Transcription factor IKZF1 (IKAROS) acts as a critical regulator of lymphoid differentiation and is frequently deleted or mutated in B-cell precursor acute lymphoblastic leukemia. IKZF1 gene defects are associated with inferior treatment outcome in both childhood and adult B-cell precursor acute lymphoblastic leukemia and occur in more than 70% of BCR-ABL1-positive and BCR-ABL1-like cases of acute lymphoblastic leukemia. Over the past few years, much has been learned about the tumor suppressive function of IKZF1 during leukemia development and the molecular pathways that relate to its impact on treatment outcome. In this review, we provide a concise overview on the role of IKZF1 during normal lymphopoiesis and the pathways that contribute to leukemia pathogenesis as a consequence of altered IKZF1 function. Furthermore, we discuss different mechanisms by which IKZF1 alterations impose therapy resistance on leukemic cells, including enhanced cell adhesion and modulation of glucocorticoid response.

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Section: Introductionmentioning

confidence: 99%

The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia

2018

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“…A recent study revealed that BTG1 serves as a tumor suppressor in B-cell precursor acute lymphoblastic leukemia (23). Similarly, another study demonstrated that BTG1 acts as a regulator of B-cell differentiation, which supports a role of BTG1 as a tumor suppressor in B-cell malignancies (24). However, a limited number of studies have performed global network analysis for BTG1, which limits the investigation of BTG1's role in DLBCL.…”

Section: Introductionmentioning

confidence: 54%

Identification of B‑cell translocation gene 1‑controlled gene networks in diffuse large B‑cell lymphoma: A study based on bioinformatics analysis

Yan

Gao

et al. 2019

Oncol Lett

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B-cell translocation gene 1 (BTG1) is a member of the BTG/transducer of Erb family. The present study evaluated the impact of BTG1 gene expression on the clinical outcome of diffuse large B-cell lymphoma (DLBCL) and investigated potential mechanisms using the Gene Expression Omnibus (GEO) database. The gene expression profile datasets GSE31312, GSE10846, GSE65420 and GSE87371 were downloaded from the GEO database. BTG1 expression and clinicopathological data were obtained from the GSE31312 dataset. In 498 cases, the expression of BTG1 in DLBCL was associated with treatment response (χ 2 =19.020; P<0.001) and International Prognostic Index score (χ 2 =5.320; P=0.025). Using the Kaplan-Meier method, it was identified that the expression of BTG1 was associated with overall survival (OS) and progression-free survival (PFS) times. Univariate and multivariate Cox regression analysis demonstrated that BTG1 was an independent predictive factor for OS and PFS. From the overlapping analysis of 407 BTG1-associated genes and 22,187 DLBCL-associated genes, 401 genes were identified as BTG1-associated DLBCL genes. Pathway analysis revealed that BTG1-associated DLBCL genes were associated with cancer progression and DLBCL signaling pathways. Subsequently, a protein-protein interaction network was constructed of the BTG1-associated genes, which consisted of 235 genes and 601 interactions. Additionally, 24 genes with high degrees in the network were identified as hub genes, which included genes associated with ‘ribosome’ [ribosomal protein (RP) L11, RPL3, RPS29, RPL19, RPL15 and RPL12], ‘cell cycle’ (ubiquitin carboxyl extension protein 52, ATM and Ras homolog family member H), ‘mitogen-activated protein kinase pathway’ (mitogen-activated protein kinase 1), ‘histone modification’ (ASH1-like protein) and ‘transcription/translation’ (eukaryotic translation initiation factor 3 subunit E, eukaryotic translation elongation factor 1 δ, transcription termination factor 1, cAMP responsive element binding protein 1 and RNA polymerase II subunit F). In conclusion, BTG1 may serve as a predictive biomarker for DLBCL prognosis. Additionally, bioinformatics analysis indicated that BTG1 may exhibit key functions in the progression and development of DLBCL.

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“…MiR-21 was previously shown to directly target the tumor suppressor gene BTG2 in HepG2 liver cancer cells [30] and following exposure to N-methyl-N-nitro-N'-nitrosoguanidine (MNNG) also in gastric cancer [31]. BTG2 is a known tumor suppressor in B-cell malignancies and acts as an important regulator of B-cell differentiation [32]. Targeting of PELI1 by miR-21 was shown in liver cells, and this interaction played a role in liver regeneration [33].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA High Throughput Loss-of-Function Screening Reveals an Oncogenic Role for miR-21-5p in Hodgkin Lymphoma

Yuan

Niu²,

Nolte

et al. 2018

Cell Physiol Biochem

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Background/Aims: Classical Hodgkin lymphoma (cHL) is among the most frequent lymphoma subtypes. The tumor cells originate from crippled germinal center (GC)-B cells that escaped from apoptosis. MicroRNAs (miRNAs) play important roles in B-cell maturation and aberrant expression of miRNAs contributes to the pathogenesis of cHL. Our aim was to identify oncogenic miRNAs relevant for growth of cHL using a high-throughput screening approach. Methods: A lentiviral pool of 63 miRNA inhibition constructs was used to identify miRNAs essential to cell growth in three cHL cell lines in duplicate. As a negative control we also infected cHL cell lines with a lentiviral barcoded empty vector pool consisting of 222 constructs. The abundance of individual constructs was followed over time by a next generation sequencing approach. The effect on growth was confirmed using individual GFP competition assays and on apoptosis using Annexin-V staining. Our previously published Argonaute 2 (Ago2) immunoprecipitation (IP) data were used to identify target genes relevant for cell growth / apoptosis. Luciferase assays and western blotting were performed to confirm targeting by miRNAs. Results: Four miRNA inhibition constructs, i.e. miR-449a-5p, miR-625-5p, let-7f-2-3p and miR-21-5p, showed a significant decrease in abundance in at least 4 of 6 infections. In contrast, none of the empty vector constructs showed a significant decrease in abundance in 3 or more of the 6 infections. The most abundantly expressed miRNA, i.e. miR-21-5p, showed significantly higher expression levels in cHL compared to GC-B cells. GFP competition assays confirmed the negative effect of miR-21-5p inhibition on HL cell growth. Annexin-V staining of cells infected with miR-21-5p inhibitor indicated a significant increase in apoptosis at day 7 and 9 after viral infection, consistent with the decrease in growth. Four miR-21-5p cell growth- and apoptosis-associated targets were AGO2-IP enriched in cHL cell lines and showed a significant decrease in expression in cHL cell lines in comparison to normal GC-B cells. For the two most abundantly expressed, i.e. BTG2 and PELI1, we confirmed targeting by miR-21-5p using luciferase assays and for PELI1 we also confirmed this at the protein level by western blotting. Conclusion: Using a miRNA loss-of-function high-throughput screen we identified four miRNAs with oncogenic effects in cHL and validated the results for the in cHL abundantly expressed miR-21-5p. MiR-21-5p is upregulated in cHL compared to GC-B cells and protects cHL cells from apoptosis possibly via targeting BTG2 and PELI1.

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Tumor suppressors BTG1 and BTG2 regulate early mouse B-cell development

Cited by 27 publications

References 15 publications

The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia

The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia

Identification of B‑cell translocation gene 1‑controlled gene networks in diffuse large B‑cell lymphoma: A study based on bioinformatics analysis

MicroRNA High Throughput Loss-of-Function Screening Reveals an Oncogenic Role for miR-21-5p in Hodgkin Lymphoma

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