Adult B-cell acute lymphoblastic leukemia cells display decreased PTEN activity and constitutive hyperactivation of PI3K/Akt pathway despite high PTEN protein levels

Gomes, Ana Margarida; Soares, Maria Augusta; Ribeiro, Patrícia Lisbôa Izetti; Caldas, Joana; Póvoa, Vanda; Martins, Leila R.; Melão, Alice; Serra‐Caetano, Ana; Sousa, Aïda Botelho de; Lacerda, João F.; Barata, João T.

doi:10.3324/haematol.2013.096438

Cited by 80 publications

(85 citation statements)

References 31 publications

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“…[20][21][22] Here we show that CK2 activity in primary B-ALL cells is similar to that in Nalm6 cells and significantly higher than in normal BM cells and normal B-cell precursors ( Figure 3A). This is in accordance with increases in CK2 activity previously observed in B-ALL and other types of cancer [39][40][41][42][43][44] and suggests that Ikaros function might be impaired due to CK2 in ALL.…”

Section: Ck2 Impairs Ikaros Tumor Suppressor Activitysupporting

confidence: 76%

“…42,47 The increased activity of CK2 in cancer is most likely due to transcription of the genes that encode its catalytic and regulatory subunits.…”

Section: Discussionmentioning

confidence: 99%

“…53 CK2 inhibition can suppress the PI3K pathway via restoration of PTEN function. 42,44,[54][55][56] Our data demonstrate an additional novel mechanism by which CK2 inhibition suppresses the PI3K pathway: by restoring Ikaros-mediated repression of multiple PI3K-promoting genes. Together, these results show that CK2 inhibition can downregulate the PI3K pathway through 2 mechanisms that are complementary but not exclusive: (1) via restoration of PTEN function and/or (2) via restoration of Ikaros function as a transcriptional regulator of genes that promote the PI3K pathway.…”

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confidence: 90%

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

Song

Gowda

Pan

et al. 2015

Blood

159

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• Ikaros controls cellular proliferation by repressing genes that regulate cell cycle progression and the PI3K pathway in leukemia.• CK2 inhibitor restores Ikaros tumor suppressor function in high-risk B-ALL with IKZF1 deletion and has a strong therapeutic effect in vivo.Ikaros (IKZF1) is a tumor suppressor that binds DNA and regulates expression of its target genes. The mechanism of Ikaros activity as a tumor suppressor and the regulation of Ikaros function in leukemia are unknown. Here, we demonstrate that Ikaros controls cellular proliferation by repressing expression of genes that promote cell cycle progression and the phosphatidylinositol-3 kinase (PI3K) pathway. We show that Ikaros function is impaired by the pro-oncogenic casein kinase II (CK2), and that CK2 is overexpressed in leukemia. CK2 inhibition restores Ikaros function as transcriptional repressor of cell cycle and PI3K pathway genes, resulting in an antileukemia effect. In high-risk leukemia where one IKZF1 allele has been deleted, CK2 inhibition restores the transcriptional repressor function of the remaining wild-type IKZF1 allele. CK2 inhibition demonstrated a potent therapeutic effect in a panel of patient-derived primary high-risk B-cell acute lymphoblastic leukemia xenografts as indicated by prolonged survival and a reduction of leukemia burden. We demonstrate the efficacy of a novel therapeutic approach for high-risk leukemia: restoration of Ikaros tumor suppressor activity via inhibition of CK2. These results provide a rationale for the use of CK2 inhibitors in clinical trials for high-risk leukemia, including cases with deletion of one IKZF1 allele. (Blood. 2015;126(15):1813-1822 Introduction Ikaros (IKZF1) activity is essential for normal hematopoiesis and immune development. [1][2][3][4] Ikaros knockout mice have severely impaired hematopoiesis, 5-7 whereas mice with the heterozygous loss of Ikaros develop T-cell leukemia. 8 In humans, impaired Ikaros activity due to the deletion or inactivating mutation of a single IKZF1 allele results in high-risk B-cell leukemia that is resistant to treatment.9-14 Ikaros regulates transcription of target genes via chromatin remodeling. [15][16][17] Ikaros activity is controlled through multiple mechanisms. Mouse studies suggest that the transcription of IKZF1 during normal hematopoiesis is regulated by a complex network. 18 However, Ikaros protein is expressed at high levels in most hematopoietic cells, and posttranslational modifications are hypothesized to play a critical role in regulating Ikaros activity. 19 Several groups have shown that phosphorylation, [19][20][21][22][23][24] sumoylation, 25 and ubiquitination 22 can regulate Ikaros function as a transcriptional repressor. However, the role of posttranslational modification in the regulation of Ikaros tumor suppressor activity in leukemia is unknown.Despite extensive global analyses of Ikaros DNA binding in normal murine hematopoietic cells, 26-28 the molecular mechanisms by which Ikaros exerts its tumor suppressor effects in human leukemia ...

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Section: Ck2 Impairs Ikaros Tumor Suppressor Activitysupporting

confidence: 76%

“…42,47 The increased activity of CK2 in cancer is most likely due to transcription of the genes that encode its catalytic and regulatory subunits.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 90%

See 1 more Smart Citation

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

Song

Gowda

Pan

et al. 2015

Blood

159

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“…23,24 Although the majority of prevalent pathogenic mechanisms affect the loss of one or both PTEN alleles, subtle changes in PTEN protein levels can have a powerful effect on cancer susceptibility and/or tumor progression, as exemplified by the Pten hypomorphic mouse model. 25 Thus, the level of functional PTEN affects tumor susceptibility, and PTEN function can be compromised at the DNA, mRNA, and/or protein levels.…”

Section: A B C Dmentioning

confidence: 99%

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

et al. 2016

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T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of developing T cells in the thymus. T-ALL is characterized by chromosomal rearrangements. These rearrangements can lead to the aberrant activation of oncogenic transcription factors by placing their genes under the control of promoters and/or enhancers of Tcell receptor genes, the BCL11B gene, or other genes; occasionally, these rearrangements can give rise to oncogenic fusion proteins. The activated oncogenic transcription factors include TAL1 and LMO2 (and related family members), TLX1, TLX3, NKX2-1, HOXA, and MEF2C; in addition, certain oncogenic fusion proteins can directly activate the HOXA or MEF2C genes.1,2 Oncogenic proteins facilitate the developmental arrest of pre-leukemic immature T cells. We previously proposed that these chromosomal rearrangements should be classified as type A aberrations, as they are generally considered to be the driving oncogenic event associated with unique expression profiles.2 Based upon their gene expression signatures, T-ALL can be classified into the following four major subtypes: ETP-ALL, TLX, proliferative, and TALLMO. [3][4][5] Maturation arrest induces a pre-leukemic condition in which additional mutations can give rise to T-ALL.1,2 These secondary mutations are not necessarily clonal events and are often selected during disease progression or post-treatment T he tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT. Based on these models and on observations in primary diagnostic samples from patients with T-cell acute lymphoblastic leukemia, we speculate that PTEN-deficient cells employ an intrinsic homeostatic mechanism in which PI3K-AKT signaling is dampened over time. As a result of this reduced PI3K-AKT signaling, the level of AKT activation may be insufficient to compensate for NOTCH1 inhibition, resulting in responsiveness to gamma-secretase inhibitors. On the other hand, de novo acquired PTEN-inactivating events in NOTCH1-dependent leukemia could result in temporary, strong activation of PI3K-AKT signaling, increased glycoly sis and glutaminolysis, and consequently gamma-secretase inhibitor resistance. Due to the central role of PTEN-AKT signaling and in the resistance to NOTCH1 inhibition, AKT inhibitors may be a promising addition to current treatment protocols for T-cell acute lymphoblastic leukemia.

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“…CK2 activity is increased in leukemia as compared with normal bone marrow (41,42). Because the results in Fig.…”

Section: Ck2 Inhibits Ikaros-mediated Repression Of Jarid1b-ourmentioning

confidence: 73%

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...

show abstract

Adult B-cell acute lymphoblastic leukemia cells display decreased PTEN activity and constitutive hyperactivation of PI3K/Akt pathway despite high PTEN protein levels

Cited by 80 publications

References 31 publications

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

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

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-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

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