Spontaneous loss of B lineage transcription factors leads to pre-B leukemia in Ebf1+/–Bcl-xLTg mice

Ramírez-Komo, Julita A.; Delaney, Martha A.; Straign, Desiree; Lukin, Kara; Tsang, Mark; Iritani, Brian M.; Hagman, James

doi:10.1038/oncsis.2017.55

Cited by 6 publications

(6 citation statements)

References 36 publications

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“…Additionally, our experiments did not examine the potential to preserve RGC function, which should be a priority in a model system better suited to clinical examination. Translational application of BCLX L gene therapy will also require evaluating the safety issues associated with long-term expression of this anti-apoptotic protein, including its possible effects on tumorigenesis [ 53 , 54 ] and increased susceptibility to viral infections [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

BCLXL gene therapy moderates neuropathology in the DBA/2J mouse model of inherited glaucoma

et al. 2021

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Axonal degeneration of retinal ganglion cells (RGCs) causes blindness in glaucoma. Currently, there are no therapies that target axons to prevent them from degenerating. Activation of the BAX protein has been shown to be the determining step in the intrinsic apoptotic pathway that causes RGCs to die in glaucoma. A putative role for BAX in axonal degeneration is less well elucidated. BCLXL (BCL2L1) is the primary antagonist of BAX in RGCs. We developed a mCherry-BCLXL fusion protein, which prevented BAX recruitment and activation to the mitochondria in tissue culture cells exposed to staurosporine. This fusion protein was then packaged into adeno-associated virus serotype 2, which was used to transduce RGCs after intravitreal injection and force its overexpression. Transduced RGCs express mCherry-BCLXL throughout their somas and axons along the entire optic tract. In a model of acute optic nerve crush, the transgene prevented the recruitment of a GFP-BAX fusion protein to mitochondria and provided long-term somal protection up to 12 weeks post injury. To test the efficacy in glaucoma, DBA/2J mice were transduced at 5 months of age, just prior to the time they begin to exhibit ocular hypertension. Gene therapy with mCherry-BCLXL did not affect the longitudinal history of intraocular pressure elevation compared to naive mice but did robustly attenuate both RGC soma pathology and axonal degeneration in the optic nerve at both 10.5 and 12 months of age. BCLXL gene therapy is a promising candidate for glaucoma therapy.

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Section: Discussionmentioning

confidence: 99%

BCLXL gene therapy moderates neuropathology in the DBA/2J mouse model of inherited glaucoma

et al. 2021

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“…Recently, another study also analyzed molecular differences between B-ALL and T-ALL and found VPREB3 as a methylation and expression signature gene [101]. EBF1 is a transcription factor involved in B-cell lineage specification and commitment [102], which explains its increased expression in B-ALL compared to T-ALL ( Table 3 ). Deletions of EBF1 have been found to be associated with B-ALL [102,103].…”

Section: Resultsmentioning

confidence: 99%

“…EBF1 is a transcription factor involved in B-cell lineage specification and commitment [102], which explains its increased expression in B-ALL compared to T-ALL ( Table 3 ). Deletions of EBF1 have been found to be associated with B-ALL [102,103]. NDST3 encodes an enzyme that plays a role in heparan sulfate metabolism [104].…”

Section: Resultsmentioning

confidence: 99%

Data-driven discovery of gene expression markers distinguishing pediatric acute lymphoblastic leukemia subtypes

Nourbakhsh,

Tom,

Schrøder Lassen

et al. 2024

Preprint

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Acute lymphoblastic leukemia (ALL), the most common cancer in children, is overall divided into two subtypes, B-cell precursor ALL (B-ALL) and T-cell ALL (T-ALL), which have different molecular characteristics. Despite massive progress in understanding the disease trajectories of ALL, ALL remains a major cause of death in children. Thus, further research exploring the biological foundations of ALL is essential. Here, we examined the diagnostic, prognostic, and therapeutic potential of gene expression data in pediatric patients with ALL. We discovered a subset of expression markers differentiating B- and T-ALL:CCN2,VPREB3,NDST3,EBF1, RN7SKP185, RN7SKP291, SNORA73B, RN7SKP255, SNORA74A, RN7SKP48, RN7SKP80, LINC00114, a novel gene (ENSG00000227706), and 7SK. The expression level of these markers all demonstrated significant effects on survival of the patients, comparing the two subtypes. We also discovered four expression subgroups in the expression data with eight genes driving separation between two of these predicted subgroups. A subset of the 14 markers could separate B- and T-ALL in an independent cohort of patients with ALL. This study can enhance our knowledge of the transcriptomic profile of different ALL subtypes.

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“…In this case, gene therapy using AAV would require careful evaluation of the safety issues related to the expression of an anti-apoptotic protein in the long term. Among these safety issues, special attention should be given to increased susceptibility to viral infections and possible effects on tumorigenesis [ 39 , 46 , 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

BCL-XL Overexpression Protects Pancreatic β-Cells against Cytokine- and Palmitate-Induced Apoptosis

Perez-Serna

Santos

Ripoll

et al. 2023

IJMS

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Diabetes is a chronic disease that affects glucose metabolism, either by autoimmune-driven β-cell loss or by the progressive loss of β-cell function, due to continued metabolic stresses. Although both α- and β-cells are exposed to the same stressors, such as proinflammatory cytokines and saturated free fatty acids (e.g., palmitate), only α-cells survive. We previously reported that the abundant expression of BCL-XL, an anti-apoptotic member of the BCL-2 family of proteins, is part of the α-cell defense mechanism against palmitate-induced cell death. Here, we investigated whether BCL-XL overexpression could protect β-cells against the apoptosis induced by proinflammatory and metabolic insults. For this purpose, BCL-XL was overexpressed in two β-cell lines—namely, rat insulinoma-derived INS-1E and human insulin-producing EndoC-βH1 cells—using adenoviral vectors. We observed that the BCL-XL overexpression in INS-1E cells was slightly reduced in intracellular Ca2+ responses and glucose-stimulated insulin secretion, whereas these effects were not observed in the human EndoC-βH1 cells. In INS-1E cells, BCL-XL overexpression partially decreased cytokine- and palmitate-induced β-cell apoptosis (around 40% protection). On the other hand, the overexpression of BCL-XL markedly protected EndoC-βH1 cells against the apoptosis triggered by these insults (>80% protection). Analysis of the expression of endoplasmic reticulum (ER) stress markers suggests that resistance to the cytokine and palmitate conferred by BCL-XL overexpression might be, at least in part, due to the alleviation of ER stress. Altogether, our data indicate that BCL-XL plays a dual role in β-cells, participating both in cellular processes related to β-cell physiology and in fostering survival against pro-apoptotic insults.

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Spontaneous loss of B lineage transcription factors leads to pre-B leukemia in Ebf1+/–Bcl-xLTg mice

Cited by 6 publications

References 36 publications

BCLXL gene therapy moderates neuropathology in the DBA/2J mouse model of inherited glaucoma

BCLXL gene therapy moderates neuropathology in the DBA/2J mouse model of inherited glaucoma

Data-driven discovery of gene expression markers distinguishing pediatric acute lymphoblastic leukemia subtypes

BCL-XL Overexpression Protects Pancreatic β-Cells against Cytokine- and Palmitate-Induced Apoptosis

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