Leukemia-associated mutations in SHIP1 inhibit its enzymatic activity, interaction with the GM-CSF receptor and Grb2, and its ability to inactivate PI3K/AKT signaling

Bräuer, H; Strauss, J; Wegner, Wiebke; Müller‐Tidow, Carsten; Horstmann, Martin; Jücker, Manfred

doi:10.1016/j.cellsig.2012.07.017

Cited by 30 publications

(39 citation statements)

References 46 publications

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Section: Ck2 Impairs Ikaros Tumor Suppressor Activitymentioning

confidence: 64%

“…Transcriptional upregulation was observed for INPP5D/SHIP-1, a gene that represses the PI3K pathway. 37 The effect of CK2 inhibition on the transcription of Ikaros target genes was markedly similar to the effect of Ikaros overexpression ( Figure , 8 OCTOBER 2015 x VOLUME 126, NUMBER 15 CK2 INHIBITION RESTORES IKAROS TUMOR SUPPRESSION 1815 For personal use only. on May 10, 2018. by guest www.bloodjournal. …”

mentioning

confidence: 72%

“…Gain or loss of function experiments as in Figure 1 revealed that Ikaros represses transcription of genes that promote the PI3K pathway but positively regulates transcription of the (INPP5D/SHIP1) gene that suppresses the PI3K pathway 37 ( Figure 2C-E). The transcription of the PIK3CD gene was particularly sensitive to the gain or loss of Ikaros function ( Figure 2C,E).…”

mentioning

confidence: 96%

“…37 Data were obtained from 2 different primary human B-ALL samples (patients 1 and 2; supplemental Table 1) by 6 separate ChIP-Seq experiments using 3 different antibodies for each primary cell sample and from the Nalm6 B-ALL cell line (representative ChIP-Seq signal maps are shown in supplemental Figures 1 and 2). Ikaros binding at the promoters of these genes determined by ChIP-Seq was confirmed by qChIP in Nalm6 ( Figures 1A and 2A), and in primary B-ALL cells ( Figures 1B and 2B).…”

mentioning

confidence: 99%

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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 Activitymentioning

confidence: 64%

mentioning

confidence: 72%

mentioning

confidence: 96%

mentioning

confidence: 99%

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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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“…Previous studies have revealed missense mutations affecting SHIP-1 (INPP5D) in 3% of AML in association with reduced 5-phosphatase function. 19,39 Although some SHIP-1 mutations (eg, SH2 [F28L] and SH3 [P1039S]) have been reported, which do not affect 5-phosphatase function, such variants were linked to loss-of-adaptor functions associated with the molecule. 19,39 Although INPP4B has been linked to a tumor suppressor role in solid cancers, the functional consequences of INPP4B expression may be tissuespecific.…”

Section: Inpp4b Overexpression Confers Resistance To Chemotherapy In mentioning

confidence: 99%

Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML

Rijal

Fleming

Cummings

et al. 2015

Blood

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Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P 3 and PtdIns(3,4)P 2 , leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P 3 3-phosphatase (PTEN), PtdIns(3,4,5)P 3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P 2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4-and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function. (Blood. 2015;125(18):2815-2824

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How does SHIP1/2 balance PtdIns(3,4)P₂ and does it signal independently of its phosphatase activity?

2013

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The number of cellular events identified as being directly or indirectly modulated by phosphoinositides dramatically increased in the recent years. Part of the complexity results from the fact that the seven phosphoinositides play second messenger functions in many different areas of growth factors and insulin signaling, cytoskeletal organization, membrane dynamics, trafficking, or nuclear signaling. PtdIns(3,4)P2 is commonly reported as a product of the SH2 domain-containing inositol 5-phosphatases 1/2 (SHIP1 and SHIP2) that dephosphorylate PtdIns(3,4,5)P3 at the 5-position. Here we discuss recent interest in PtdIns(3,4)P2 signaling highlighting its involvement in key cellular mechanisms such as cell adhesion, migration, and cytoskeletal regulation. We question and discuss the involvement of SHIP2 either as a PI 5-phosphatase or as a scaffold protein in insulin signaling, cytoskeletal dynamics, and endocytosis of growth factor receptors.

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Leukemia-associated mutations in SHIP1 inhibit its enzymatic activity, interaction with the GM-CSF receptor and Grb2, and its ability to inactivate PI3K/AKT signaling

Cited by 30 publications

References 46 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

Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML

How does SHIP1/2 balance PtdIns(3,4)P₂ and does it signal independently of its phosphatase activity?

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Leukemia-associated mutations in SHIP1 inhibit its enzymatic activity, interaction with the GM-CSF receptor and Grb2, and its ability to inactivate PI3K/AKT signaling

Cited by 30 publications

References 46 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

Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML

How does SHIP1/2 balance PtdIns(3,4)P2 and does it signal independently of its phosphatase activity?

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How does SHIP1/2 balance PtdIns(3,4)P₂ and does it signal independently of its phosphatase activity?