Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia

Song, Chunhua; Gowda, Chandrika; Pan, Xiaokang; Ding, Yali; Tong, Yongqing; Tan, Bi Hua; Wang, Haijun; Muthusami, Sunil; Ge, Zheng; Sachdev, Mansi; Amin, Shantu; Desai, Dhimant; Gowda, Krishne; Robertson, Gavin P.; Schjerven, Hilde; Müschen, Markus; Payne, Kimberly J.; Dovat, Sinisa

doi:10.1182/blood-2015-06-651505

Cited by 83 publications

(173 citation statements)

References 59 publications

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“…More importantly, this suggests that CK2 inhibition can enhance the activity of the remaining wild type Ikaros allele and restore Ikaros tumor suppressor function, at least with respect to the regulation of JARID1B transcription. Recently, CK2 inhibition has been shown to restore Ikaros-mediated repression of the cell cycle-promoting genes and genes that regulate the PI3K pathway in high-risk ALL with deletion of a single Ikaros allele, which supports our proposed model of JARID1B regulation by CK2 and Ikaros (61). CK2 is considered a target for treatment in various types of malignancies, and a phase I clinical trial with CK2 inhibitors has recently been completed for solid tumors.…”

Section: Discussionsupporting

confidence: 58%

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

Wang

Song

Ding

et al. 2016

Journal of Biological Chemistry

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Impaired function of the Ikaros (IKZF1) protein is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL). The mechanisms of Ikaros tumorsuppressor activity in leukemia are unknown. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. Here, we report that Ikaros represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B). Transcriptional repression of JARID1B is associated with increased global levels of H3K4 trimethylation. Ikaros-mediated repression of JARID1B is dependent on the activity of the histone deacetylase, HDAC1, which binds to the upstream regulatory element of JARID1B in complex with Ikaros. In leukemia, JARID1B is overexpressed, and its inhibition results in cellular growth arrest. Ikaros-mediated repression of JARID1B in leukemia is impaired by pro-oncogenic casein kinase 2 (CK2). Inhibition of CK2 results in increased binding of the Ikaros-HDAC1 complex to the promoter of JARID1B, with increased formation of trimethylated histone H3 lysine 27 and decreased histone H3 Lys-9 acetylation. In cases of high-risk B-ALL that carry deletion of one Ikaros (IKZF1) allele, targeted inhibition of CK2 restores Ikaros binding to the JARID1B promoter and repression of JARID1B. In summary, the presented data suggest a mechanism through which Ikaros and HDAC1 regulate the epigenetic signature in leukemia: via regulation of JARID1B transcription. The presented data identify JARID1B as a novel therapeutic target in B-ALL and provide a rationale for the use of CK2 inhibitors in the treatment of high-risk B-ALL.IKZF1 encodes the Ikaros DNA-binding zinc finger protein (1-4). Ikaros is essential for normal hematopoiesis and acts as a tumor suppressor (5, 6). In humans, deletion of a single Ikaros allele is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL) 3 that is characterized by resistance to chemotherapy and poor prognosis (7-9). Alterations in the Ikaros have also been associated with T cell ALL (10, 11) and myeloid leukemias (12-16). Ikaros regulates transcription of its target genes via chromatin remodeling (9). Ikaros has been shown to directly bind histone deacetylases HDAC1 and HDAC2 and to associate with the chromatin remodeling complex NuRD through interaction with the Mi-2 protein (9, 17).Ikaros is hypothesized to recruit chromatin remodeling complexes to the regulatory elements of its target genes, resulting in chromatin modifications (primarily histone deacetylation) and transcriptional repression or activation of its target genes (18 -20). Mechanisms of Ikaros-mediated repression that are independent of histone deacetylase have also been described (18, 3 The abbreviations used are: B-ALL, B-cell precursor acute lymphoblastic leukemia; CK2, casein kinase 2; TSS, transcriptional start site; ALL, acute lymphoblastic leukemia; TBB, 4,5,6,7-tetrabromobenzotriazole; IK haploid , Ikaros haploinsufficiency; Ikaros-CTS, C terminus o...

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Section: Discussionsupporting

confidence: 58%

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

Wang

Song

Ding

et al. 2016

Journal of Biological Chemistry

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“…17 Many of the CK2 described substrates are proteins involved in the regulation of cell survival, with compiled evidence that the reduction of CK2 activity or expression leads to cell death, in such a way that CK2 is considered to have mainly a pro-survival and proliferative function. In agreement with these features, CK2 is significantly and consistently overexpressed in solid 18 and hematological [19][20][21][22] tumor cells, including T-ALL. 23 Primary T-ALL cells collected from diagnostic patients display basal hyperactivation of the PI3K/Akt signaling pathway.…”

Section: Introductionsupporting

confidence: 60%

Optimal interleukin-7 receptor-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on casein kinase 2 activity

et al. 2016

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I nterleukin-7 and interleukin-7 receptor are essential for normal T-cell development and homeostasis, whereas excessive interleukin-7/interleukin-7 receptor-mediated signaling promotes leukemogenesis. The protein kinase, casein kinase 2, is overexpressed and hyperactivated in cancer, including T-cell acute lymphoblastic leukemia. Herein, we show that while interleukin-7 had a minor but significant positive effect on casein kinase 2 activity in leukemia T-cells, casein kinase 2 activity was mandatory for optimal interleukin-7/ interleukin-7 receptor-mediated signaling. Casein kinase 2 pharmacological inhibition impaired signal transducer and activator of transcription 5 and phosphoinositide 3-kinase/v-Akt murine thymoma viral oncogene homolog 1 pathway activation triggered by interleukin-7 or by mutational activation of interleukin-7 receptor. By contrast, forced expression of casein kinase 2 augmented interleukin-7 signaling in human embryonic kidney 293T cells reconstituted with the interleukin-7 receptor machinery. Casein kinase 2 inactivation prevented interleukin-7-induced B-cell lymphoma 2 upregulation, maintenance of mitochondrial homeostasis and viability of T-cell acute lymphoblastic leukemia cell lines and primary leukemia cells collected from patients at diagnosis. Casein kinase 2 inhibition further abrogated interleukin-7-mediated cell growth and upregulation of the transferrin receptor, and blocked cyclin A and E upregulation and cell cycle progression. Notably, casein kinase 2 was also required for the viability of mutant interleukin-7 receptor expressing leukemia T-cells. Overall, our study identifies casein kinase 2 as a major player in the effects of interleukin-7 and interleukin-7 receptor in T-cell acute lymphoblastic leukemia. This further highlights the potential relevance of targeting casein kinase 2 in this malignancy.

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“…Hence, targeting IKZF1 by, for example, casein kinase II (66) or FAK inhibitors (65), may be useful in targeting this dormancy stage. Similarly, we speculate that leukemic cells carrying CRLF2 rearrangements-and, hence, expressing the TSLP receptor-may survive chemotherapy during complete remission by interacting with TSLP-producing cells in the bonemarrow niche.…”

Section: Discussionmentioning

confidence: 99%

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Schwartzman

Savino

Gombert

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DSALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/ RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are "relapse driving." We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2 pos DSALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2 pos , Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT "hypersignaling" may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.C hildren with Down syndrome (DS) are at a markedly increased risk for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (1). The poor survival of DS-ALL compared with ALL in children without DS ("sporadic" ALL) is related to increased treatment toxicity and to increased incidence of relapse (2). Thus, better therapy is needed for these patients.Previous studies by our group and others revealed differences between the genetics of DS-ALLs and of sporadic ALLs (3-6). The typical cytogenetic subgroups, ETV6-RUNX1 and hyperdiploid ALLs, are less common in DS-ALLs. Acquired somatic activation of the thymic stromal lymphopoietin (TSLP) pathway are present at diagnosis in about half of DS-ALLs. Aberrant expression of cytokine receptor-like factor 2 (CRLF2) in these leukemias is caused by chromosomal rearrangements consisting either of a microdeletion on chromosome X, juxtaposing the promoter of P2RY8 with the coding region of CRLF2, or by a translocation of CRLF2 into the Ig heavy chain (IgH) locus. CRLF2 heterodimerizes with IL7 receptor-α (IL7R) to form the receptor to TSLP (reviewed in ref. 7). TSLP receptors signal by activation of the JAK-STAT pathway. Interestingly, in the majority of DS-ALLs, SignificanceChildren with Down syndrome are at increased risk ...

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Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia

Cited by 83 publications

References 59 publications

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

Optimal interleukin-7 receptor-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on casein kinase 2 activity

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

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