Cellular signaling and epigenetic regulation of gene expression in leukemia

Gowda, Chandrika; Song, Chunhua; Ding, Yali; Iyer, Soumya; Dhanyamraju, Pavan Kumar; McGrath, Mary; Bamme, Yevgeniya; Soliman, Mario; Kane, Shriya; Payne, Joseph Frank; Dovat, Sinisa

doi:10.1016/j.jbior.2019.100665

Cited by 22 publications

(16 citation statements)

References 133 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…CK2 has a pretty large number of substrates (Meggio and Pinna, 2003), and recently, CK2 was demonstrated to phosphorylate histone chaperone Spt6 that is associated with RNA polymerase II and therefore promotes DNA transcription (Dronamraju et al, 2018). Since CK2 is an oncogenic enzyme involved in epigenetic processes (reviewed by Gowda et al, 2019), further targets need to be unraveled. Here, we focused on K Ca 2 channel-mediated mechanisms.…”

Section: Disease Modification After Transient Ck2 Inhibition In Vivomentioning

confidence: 99%

CK2 Inhibition Prior to Status Epilepticus Persistently Enhances KCa2 Function in CA1 Which Slows Down Disease Progression

Schulze

Müller

Guli

et al. 2020

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Purpose: Epilepsy therapy is currently based on anti-seizure drugs that do not modify the course of the disease, i.e., they are not anti-epileptogenic in nature. Previously, we observed that in vivo casein kinase 2 (CK2) inhibition with 4,5,6,7-tetrabromotriazole (TBB) had anti-epileptogenic effects in the acute epilepsy slice model. Methods: Here, we pretreated rats with TBB in vivo prior to the establishment of a pilocarpine-induced status epilepticus (SE) in order to analyze the long-term sequelae of such a preventive TBB administration. Results: We found that TBB pretreatment delayed onset of seizures after pilocarpine and slowed down disease progression during epileptogenesis. This was accompanied with a reduced proportion of burst firing neurons in the CA1 area. Western blot analyses demonstrated that CA1 tissue from TBB-pretreated epileptic animals contained significantly less CK2 than TBB-pretreated controls. On the transcriptional level, TBB pretreatment led to differential gene expression changes of K Ca 2.2, but also of HCN1 and HCN3 channels. Thus, in the presence of the HCN channel blocker ZD7288, pretreatment with TBB rescued the afterhyperpolarizing potential (AHP) as well as spike frequency adaptation in epileptic animals, both of which are prominent functions of K Ca 2 channels. Conclusion: These data indicate that TBB pretreatment prior to SE slows down disease progression during epileptogenesis involving increased K Ca 2 function, probably due to a persistently decreased CK2 protein expression.

show abstract

Section: Disease Modification After Transient Ck2 Inhibition In Vivomentioning

confidence: 99%

CK2 Inhibition Prior to Status Epilepticus Persistently Enhances KCa2 Function in CA1 Which Slows Down Disease Progression

Schulze

Müller

Guli

et al. 2020

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…IKAROS plays a central role in hematopoiesis, lymphoid development, and T cell differentiation [ 7 , 8 ]. Recently published studies have established IKAROS as a global epigenetic regulator of gene expression in T-ALL [ 9 , 10 ]. Global epigenomic analyses in T-ALL have shown that IKAROS functions as a tumor suppressor by widespread sequence-specific DNA binding to regulatory elements of its target genes and recruitment of histone-remodeling complexes, thereby repressing or activating gene transcription [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2

Dovat

Song

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS’s novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes that are likely to be directly regulated by IKAROS. Here, we report the transcriptional regulation of two genes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE), by IKAROS in T-ALL. PIK3CD encodes the protein p110δ subunit of phosphoinositide 3-kinase (PI3K). The PI3K/AKT pathway is frequently dysregulated in cancers, including T-ALL. IKAROS binds to the promoter regions of PIK3CD and PIKFYVE and reduces their transcription in primary T-ALL. Functional analysis demonstrates that IKAROS functions as a transcriptional repressor of both PIK3CD and PIKFYVE. Protein kinase CK2 (CK2) is a pro-oncogenic kinase that is overexpressed in T-ALL. CK2 phosphorylates IKAROS, impairs IKAROS’s DNA-binding ability, and functions as a repressor of PIK3CD and PIKFYVE. CK2 inhibition results in increased IKAROS binding to the promoters of PIK3CD and PIKFYVE and the transcriptional repression of both these genes. Overall, the presented data demonstrate for the first time that in T-ALL, CK2 hyperactivity contributes to PI3K signaling pathway upregulation, at least in part, through impaired IKAROS transcriptional regulation of PIK3CD and PIKFYVE. Targeting CK2 restores IKAROS’s regulatory effects on the PI3K oncogenic signaling pathway.

show abstract

“…IKAROS is a zinc finger protein that binds to and regulates DNA transcription [34,35]. It has recently been implicated as an epigenetic regulator [36] with the ability to induce active enhancers and 4 of 17 super-enhancers [37]. IKAROS plays key roles in hematopoiesis and lymphopoiesis [38,39] and is of importance for B-ALL as it is essential for the differentiation of B cell precursors [40].…”

Section: Role Of Lymphoid Transcription Factors Ikaros and Pax5mentioning

confidence: 99%

The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia

Shiraz

Payne

Muffly

2020

IJMS

View full text Add to dashboard Cite

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk B-cell Acute Lymphoblastic Leukemia (B-ALL) characterized by a gene expression profile similar to Ph-positive B-ALL but lacking the BCR-ABL1 translocation. The molecular pathogenesis of Ph-like B-ALL is heterogenous and involves aberrant genomics, receptor overexpression, kinase fusions, and mutations leading to kinase signaling activation, leukemogenic cellular proliferation, and differentiation blockade. Testing for the Ph-like signature, once only a research technique, is now available to the clinical oncologist. The plethora of data pointing to poor outcomes for this ALL subset has triggered investigations into the role of targeted therapies, predominantly involving tyrosine kinase inhibitors that are showing promising results.

show abstract

Cellular signaling and epigenetic regulation of gene expression in leukemia

Cited by 22 publications

References 133 publications

CK2 Inhibition Prior to Status Epilepticus Persistently Enhances KCa2 Function in CA1 Which Slows Down Disease Progression

CK2 Inhibition Prior to Status Epilepticus Persistently Enhances KCa2 Function in CA1 Which Slows Down Disease Progression

Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2

The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia

Contact Info

Product

Resources

About