Epigenetic regulation of gene expression by Ikaros, HDAC1 and Casein Kinase II in leukemia

Song, Chunhua; Pan, Xiaokang; Ge, Zheng; Gowda, Chandrika; Ding, Yali; Li, H; Li, Z; Yochum, Gregory S.; Müschen, Markus; Li, Q; Payne, Kimberly J.; Dovat, Sinisa

doi:10.1038/leu.2015.331

Cited by 47 publications

(82 citation statements)

References 15 publications

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“…We found Ikaros regulates expression of its targets through chromatin remodeling in ALL15161718. We also found CK2-inhibitors increase tumor suppressor activity of Ikaros and act as a functional activator of Ikaros151617. Our ChIP-seq data indicate Ikaros binding peaks in the promoter region of DNM2 .…”

supporting

confidence: 53%

“…ChIP-seq data identified Ikaros binding peaks in the DNM2 promoter region in Nalm6 B-ALL (Fig. 2A) and primary B-cell ALL cells (Supplemental Figure 3)1516. Ikaros binding was confirmed by qChIP assay (Fig.…”

Section: Resultsmentioning

confidence: 78%

“…Recently, we reported the Ikaros global binding profiling in ALL cells. We found Ikaros regulates expression of its targets through chromatin remodeling in ALL15161718. We also found CK2-inhibitors increase tumor suppressor activity of Ikaros and act as a functional activator of Ikaros151617.…”

mentioning

confidence: 64%

“…We reported Ikaros regulates gene expression through chromatin remodeling16. To further explore the epigenetic mechanism by which Ikaros regulates DNM2 expression we performed ChIP assay and amplified the resulting DNM2 promoter sequences.…”

Section: Resultsmentioning

confidence: 99%

“…qChIP assays were performed by incubating chromatin with antibodies against Ikaros151617, H3K9me3 (Abcam, Cambridge, MA, USA) or normal rabbit IgG (Abcam) as a control15161748. Enrichment of the ChIP sample over input was evaluated by qPCR with ≥ 3 replicates using specific primers in the promoter region of DNM2 (forward: 5′-ACCGCGGGATGGAAGAG-3′, reverse: 5′-TGAAGGCGTCCTGCAGTTT-3′).…”

Section: Methodsmentioning

confidence: 99%

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Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia

Han

et al. 2016

Sci Rep

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Dynamin-2 (DNM2) is a GTPase essential for intracellular vesicle formation and trafficking, cytokinesis and receptor endocytosis. Mutations in DNM2 are common in early T-cell precursor acute lymphoblastic leukemia. However, DNM2 expression in other types of ALL are not reported. We studied DNM2 mRNA level in adults with B- and T-cell ALL. We found DNM2 is more highly expressed compared with normals in both forms of ALL. High DNM2 expression is associated with some clinical and laboratory features, inferior outcomes and with leukaemia cell proliferation. We also found Ikaros directly binds the DNM2 promoter and suppresses DNM2 expression. Consequently IKZF1 deletion is associated with high DNM2 expression. Conversely, casein kinase-2 (CK2)-inhibitor increases Ikaros function thereby inhibiting DNM2 expression. Inhibiting DNM2 suppresses proliferation of leukemia cells and synergizes with CK2 inhibition. Our data indicate high DNM2 expression is associated with Ikaros dysregulation and may be important in the development of B-ALL.

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supporting

confidence: 53%

Section: Resultsmentioning

confidence: 78%

mentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia

Han

et al. 2016

Sci Rep

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Notch in Leukemia

McCarter

Wang

Chiang

2018

Advances in Experimental Medicine and Biology

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Notch is commonly activated in lymphoid malignancies through ligand-independent and ligand-dependent mechanisms. In T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), ligand-independent activation predominates. Negative Regulatory Region (NRR) mutations trigger supraphysiological Notch1 activation by exposing the S2 site to proteolytic cleavage in the absence of ligand. Subsequently, cleavage at the S3 site generates the activated form of Notch, intracellular Notch (ICN). In contrast to T-ALL, in mature lymphoid neoplasms such as chronic lymphocytic leukemia (CLL), the S2 cleavage site is exposed through ligand-receptor interactions. Thus, agents that disrupt ligand-receptor interactions might be useful for treating these malignancies. Notch activation can be enhanced by mutations that delete the C-terminal proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST) domain. These mutations do not activate the Notch pathway per se, but rather impair degradation of ICN. In this chapter, we review the mechanisms of Notch activation and the importance of Notch for the genesis and maintenance of lymphoid malignancies. Unfortunately, targeting the Notch pathway with pan-Notch inhibitors in clinical trials has proven challenging. These clinical trials have encountered dose-limiting on-target toxicities and primary resistance. Strategies to overcome these challenges have emerged from the identification and improved understanding of direct oncogenic Notch target genes. Other strategies have arisen from new insights into the "nuclear context" that selectively directs Notch functions in lymphoid cancers. This nuclear context is created by factors that co-bind ICN at cell-type specific transcriptional regulatory elements. Disrupting the functions of these proteins or inhibiting downstream oncogenic pathways might combat cancer without the intolerable side effects of pan-Notch inhibition.

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Relationship between post-surgery detection of methylated circulating tumor DNA with risk of residual disease and recurrence-free survival

Murray¹,

Symonds

Young

et al. 2018

J Cancer Res Clin Oncol

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Epigenetic regulation of gene expression by Ikaros, HDAC1 and Casein Kinase II in leukemia

Cited by 47 publications

References 15 publications

Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia

Targeting High Dynamin-2 (DNM2) Expression by Restoring Ikaros Function in Acute Lymphoblastic Leukemia

Notch in Leukemia

Relationship between post-surgery detection of methylated circulating tumor DNA with risk of residual disease and recurrence-free survival

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