Differential PAX5 levels promote malignant B-cell infiltration, progression and drug resistance, and predict a poor prognosis in MCL patients independent of CCND1

Teo, Albert E.; Chen, Z.; Miranda, Roberto N.; McDonnell, Timothy J.; Medeiros, L. Jeffrey; McCarty, Nami

doi:10.1038/leu.2015.140

Cited by 23 publications

(20 citation statements)

References 52 publications

(50 reference statements)

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“…Upregulation of BMI1 and downregulation of miR-16 in the MCL side population (SP) reduces apoptosis in these cells [66]. Downregulation of PAX5, a member of the paired box (PAX) family of transcription factors, correlates with an aggressive, highly drug-resistant, phenotype predictive of poor prognosis [67]. Overexpression of JARID1B and reduced histone H3K4 tri-methylation were associated with MCL and therefore, depletion of JARID1B caused up-regulation of histone acetylation of H3 and inactivation of Cyclin D1 leading to apoptosis of MCL cells [68].…”

Section: Role Of Biomarkers In Detection Diagnosis and Therapeutic mentioning

confidence: 99%

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

et al. 2016

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Despite advances in the development of clinical agents for treating Mantle Cell Lymphoma (MCL), treatment of MCL remains a challenge due to complexity and frequent relapse associated with MCL. The incorporation of conventional and novel diagnostic approaches such as genomic sequencing have helped improve understanding of the pathogenesis of MCL, and have led to development of specific agents targeting signaling pathways that have recently been shown to be involved in MCL. In this review, we first provide a general overview of MCL and then discuss about the role of biomarkers in the pathogenesis, diagnosis, prognosis, and treatment for MCL. We attempt to discuss major biomarkers for MCL and highlight published and ongoing clinical trials in an effort to evaluate the dominant signaling pathways as drugable targets for treating MCL so as to determine the potential combination of drugs for both untreated and relapse/refractory cases. Our analysis indicates that incorporation of biomarkers is crucial for patient stratification and improve diagnosis and predictability of disease outcome thus help us in designing future precision therapies. The evidence indicates that a combination of conventional chemotherapeutic agents and novel drugs designed to target specific dysregulated signaling pathways can provide the effective therapeutic options for both untreated and relapse/refractory MCL.

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Section: Role Of Biomarkers In Detection Diagnosis and Therapeutic mentioning

confidence: 99%

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

et al. 2016

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“…Mononuclear cells were isolated from MCL patient apheresis blood or BM using standard Ficoll gradient separation methods. CD19 + B cells from MCL patients or healthy donors were isolated as previously described (26). Primary cells were cultured in complete RPMI1640 medium for further analysis.…”

Section: Methodsmentioning

confidence: 99%

“…The DNA-binding activities of NF-kB components, TG2 enzymatic activity and IL-6 levels were determined by ELISA assays, as previously described (11,26). …”

Section: Methodsmentioning

confidence: 99%

“…The STAT3 pathway was detected as previously described (26). Total harvested cells were lysed to perform immunoblots as previously reported (27).…”

Section: Methodsmentioning

confidence: 99%

“…Mice were sacrificed four weeks post injection and tumors, spleens and bone marrows were isolated for further analysis. The volumes of tumors and spleens were measured as previously described (26). …”

Section: Methodsmentioning

confidence: 99%

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TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy

et al. 2016

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Expression of the transglutaminase TG2 has been linked to constitutive activation of NF-kB and chemotherapy resistance in mantle cell lymphoma (MCL) cells. TG2 forms complexes with NF-kB components, but mechanistic insights that could be used to leverage therapeutic responses has been lacking. In the present study, we address this issue with the discovery of an unexpected role for TG2 in triggering autophagy in drug-resistant MCL cells through induction of IL-6. CRISPR-mediated silencing of TG2 delayed apoptosis while overexpressing TG2 enhanced tumor progression. Under stress, TG2 and IL-6 mediate enhanced autophagy formation to promote MCL cell survival. Interestingly, the autophagy product ATG5 involved in autophagosome elongation positively regulated TG2/NF-kB/IL-6 signaling, suggesting a positive feedback loop. Our results uncover an interconnected network of TG2/NF-kB and IL-6/STAT3 signaling with autophagy regulation in MCL cells, the disruption of which may offer a promising therapeutic strategy.

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Overexpression of heme oxygenase‐1 in microenvironment mediates vincristine resistance of B‐cell acute lymphoblastic leukemia by promoting vascular endothelial growth factor secretion

Wang

Lü

et al. 2019

J of Cellular Biochemistry

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Chemoresistance often causes treatment failure of B‐cell acute lymphoblastic leukemia (B‐ALL). However, the mechanism remains unclear at present. Herein, overexpression of heme oxygenase‐1 (HO‐1) was found in the bone marrow stromal cells (BMSCs) from B‐ALL patients developing resistance to vincristine (VCR), a chemotherapeutic agent. Two B‐ALL cell lines Super B15 and CCRF‐SB were cocultured with BMSCs transfected with lentivirus to regulate the expression of HO‐1. Silencing HO‐1 expression in BMSCs increased the apoptotic rates of B‐ALL cell lines induced by VCR, whereas upregulating HO‐1 expression reduced the rate. Cell cycle can be arrested in the G2/M phase by VCR. In contrast, B‐ALL cells were arrested in the G0/G1 phase due to HO‐1 overexpression in BMSCs, which avoided damage from the G2/M phase. Vascular endothelial growth factor (VEGF) in BMSCs, as a key factor in the microenvironment‐associated chemoresistance, was also positively coexpressed with HO‐1. VEGF secretion was markedly increased in BMSCs with HO‐1 upregulation but decreased in BMSCs with HO‐1 silencing. B‐ALL cell lines became resistant to VCR when cultured with VEGF recombinant protein, so VEGF secretion induced by HO‐1 expression may promote the VCR resistance of B‐ALL cells. As to the molecular mechanism, the PI3K/AKT pathway mediated regulation of VEGF by HO‐1. In conclusion, this study clarifies a mechanism by which B‐ALL is induced to resist VCR through HO‐1 overexpression in BMSCs, and provides a novel strategy for overcoming VCR resistance in clinical practice.

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Differential PAX5 levels promote malignant B-cell infiltration, progression and drug resistance, and predict a poor prognosis in MCL patients independent of CCND1

Cited by 23 publications

References 52 publications

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy

Overexpression of heme oxygenase‐1 in microenvironment mediates vincristine resistance of B‐cell acute lymphoblastic leukemia by promoting vascular endothelial growth factor secretion

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