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Christian Steinebach, Stefanie Lindner, Namrata D Udeshi, Deepak C Mani, Hannes Kehm, Simon Köpff, Steven A Carr, Michael Gütschow, Jan Kronke
The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide, all approved for the treatment of multiple myeloma, induce targeted ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3) via the cereblon (CRBN) E3 ubiquitin ligase. IMiD-based proteolysis targeting chimeras (PROTACs) can efficiently recruit CRBN to a protein of interest leading to its ubiquitination and proteasomal degradation. By linking two pomalidomide molecules, we designed homobifunctional, so-called Homo-PROTACs and investigated their ability to induce self-directed ubiquitination and degradation...
August 17, 2018: ACS Chemical Biology
Wen-Jing Fan, Zhi-Qiao Fan, Mei-Juan Yang, Yao-Zhu Pan, Hai Bai
Cereblon(CRBN) is a brain-associated protein with ionic protease activity, which interacts with DNA damage-binding protein-1 (DDB1), Cullin 4 (Cul4A or Cul4B), and regulator of Cullins 1 (RoC1) to form the functional E3 ubiquitin ligase complex(CRBN-CRL4) that performs proteolysis via the ubiquitin-proteasome pathway. And CRBN is a necessary target protein for the anti-myeloma effect of immunomodulators. The combination of lenalidomide and CRBN recruited a new substrate that binds to the CRBN-CRL4 complex, leading to increased ubiquitination and proteasome-dependent degradation, thus resulting in anti-myeloma activity...
August 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Xue-Fei Zhao, Hong-Yan Wang, Xu Zhao, Huan-Chen Cheng, Wei Li, Sheng-Wei Liu, Lin Qiu, Jun Ma
OBJECTIVE: To retrospectively analyze the immunophenotyping, fusion gene and gene mutation of 30 acute lymphoblastic leukemia (ALL) cases and to investigate the relationship between the analysis results and the clinical therapeutic effect and prognosis. METHODS: Thirty All phtients were collected from the First Hospital of Harbin, Institute of Hematology and Oncology Department of Pediatrics from August 2015 to June 2016. According to the classification of FAB standard, 27 cases were B system ALL, 3 cases were T system ALL...
August 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Yingying Wu, Fangfang Qi, Dan Song, Zitian He, Zejie Zuo, Yunjie Yang, Qiongliang Liu, Saisai Hu, Xiao Wang, Xiaona Zheng, Junhua Yang, Qunfang Yuan, Juntao Zou, Kaihua Guo, Zhibin Yao
BACKGROUND: Prenatal infection is a substantial risk factor for neurodevelopmental disorders such as autism in offspring. We have previously reported that influenza vaccination (VAC) during early pregnancy contributes to neurogenesis and behavioral function in offspring. RESULTS: Here, we probe the efficacy of VAC pretreatment on autism-like behaviors in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) mouse model. We show that VAC improves abnormal fetal brain cytoarchitecture and lamination, an effect associated with promotion of intermediate progenitor cell differentiation in MIA fetal brain...
August 13, 2018: Journal of Neuroinflammation
Talha Khan Burki
No abstract text is available yet for this article.
August 2, 2018: Lancet Oncology
Emma C Fink, Marie McConkey, Dylan N Adams, Saurav D Haldar, James A Kennedy, Andrew A Guirguis, Namrata D Udeshi, D R Mani, Michelle Chen, Brian Liddicoat, Tanya Svinkina, Andrew T Nguyen, Steven A Carr, Benjamin L Ebert
Thalidomide and its derivatives, lenalidomide and pomalidomide, are clinically effective treatments for multiple myeloma and myelodysplastic syndrome with del(5q). These molecules lack activity in murine models, limiting investigation of their therapeutic activity or toxicity in vivo Here, we report the development of a mouse model that is sensitive to thalidomide derivatives due to a single amino acid change in the direct target of thalidomide derivatives, Crbn. In human cells, thalidomide and its analogs bind CRBN and recruit protein targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and subsequent degradation by the proteasome...
July 31, 2018: Blood
Allen Eng Juh Yeoh, Yi Lu, Winnie Hui Ni Chin, Edwynn Kean Hui Chiew, Evelyn Huizi Lim, Zhenhua Li, Shirley Kow Yin Kham, Yiong Huak Chan, Wan Ariffin Abdullah, Hai Peng Lin, Lee Lee Chan, Joyce Ching Mei Lam, Poh Lin Tan, Thuan Chong Quah, Ah Moy Tan, Hany Ariffin
Purpose Although IKZF1 deletion ( IKZF1del ) confers a higher risk of relapse in childhood B-cell acute lymphoblastic leukemia (B-ALL), it is uncertain whether treatment intensification will reverse this risk and improve outcomes. The Malaysia-Singapore ALL 2010 study (MS2010) prospectively upgraded the risk assignment of patients with IKZF1del to the next highest level and added imatinib to the treatment of all patients with BCR- ABL1 fusion. Patients and Methods In total, 823 patients with B-ALL treated in the Malyasia-Singapore ALL 2003 study (MS2003; n = 507) and MS2010 (n = 316) were screened for IKZF1del using the multiplex ligation-dependent probe amplification assay...
July 25, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Quinlan L Sievers, Jessica A Gasser, Glenn S Cowley, Eric S Fischer, Benjamin L Ebert
Lenalidomide mediates the ubiquitination and degradation of IKZF1, IKZF3 and CK1α by facilitating their interaction with cereblon (CRBN), the substrate receptor for the CRL4CRBN E3 ubiquitin ligase. Through this mechanism, lenalidomide is a clinically effective treatment for multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q (del(5q) MDS). To identify the cellular machinery required for lenalidomide-induced CRL4CRBN activity, we performed a positive selection, genome-scale CRISPR-Cas9 screen in a lenalidomide-sensitive myeloma cell line...
July 24, 2018: Blood
Jiye Liu, Tianyu Song, Wenrong Zhou, Lijie Xing, Su Wang, Matthew Ho, Zhengang Peng, Yu-Tzu Tai, Teru Hideshima, Kenneth C Anderson, Yong Cang
Immunomodulatory drugs (IMiDs) including lenalidomide and pomalidomide bind cereblon (CRBN) and activate the CRL4CRBN ubiquitin ligase to trigger proteasomal degradation of the essential transcription factors IKZF1 and IKZF3 and multiple myeloma (MM) cytotoxicity. We have shown that CRBN is also targeted for degradation by SCFFbxo7 ubiquitin ligase. In the current study, we explored the mechanisms underlying sensitivity of MM cells to IMiDs using genome-wide CRISPR-Cas9 screening. We validate that CSN9 signalosome complex, a deactivator of Cullin-RING ubiquitin ligase, inhibits SCFFbxo7 E3 ligase-mediated CRBN degradation, thereby conferring sensitivity to IMiDs; conversely, loss of function of CSN9 signalosome activates SCFFbxo7 complex, thereby enhancing degradation of CRBN and conferring IMiD resistance...
July 19, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Wen-Yong Kuang, Min-Cui Zheng, Wan-Li Li, Hai-Xia Yang, Ben-Shan Zhang, Pan Wu
OBJECTIVE: To study the effects of minimal residual disease (MRD) level on day 33 of remission induction and IKZF1 genotype on the survival of children with B-lineage acute lymphoblastic leukemia (B-ALL). METHODS: A total of 152 children with newly-diagnosed B-ALL who had complete remission after the first cycle of the chemotherapy and had complete follow-up information were enrolled in this study. According to the MRD detection by flow cytometry on day 33 of remission induction, they were divided into three groups: standard-risk (SR) group (MRD <10-4 ; n=60), intermediate-risk (IR) group (10-4 ≤ MRD <10-2 ; n=55), and high-risk (HR) group (MRD ≥10-2 ; n=37)...
July 2018: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
David H Murray, Erin L Symonds, Graeme P Young, Susan Byrne, Philippa Rabbitt, Amitesh Roy, Kathryn Cornthwaite, Christos S Karapetis, Susanne K Pedersen
PURPOSE: Methylation in IKZF1 and BCAT1 are common events in colorectal cancer (CRC). They are often detected in blood as circulating tumor DNA (ctDNA) at diagnosis and disappear after surgery in most CRC patients. A prospective study was conducted to determine the relationship between detection of these markers following surgery and risk for residual disease and for recurrence. METHODS: ctDNA status with methylated BCAT1 and IKZF1 was determined within 12 months of surgical resection of CRC, and was related to presence of or risk for residual disease (margins involved, metastases present or nature of node involvement), and to recurrence-free survival...
July 10, 2018: Journal of Cancer Research and Clinical Oncology
Marija Klasić, Dora Markulin, Aleksandar Vojta, Ivana Samaržija, Ivan Biruš, Paula Dobrinić, Nicholas T Ventham, Irena Trbojević-Akmačić, Mirna Šimurina, Jerko Štambuk, Genadij Razdorov, Nicholas A Kennedy, Jack Satsangi, Ana M Dias, Salome Pinho, Vito Annese, Anna Latiano, Renata D'Inca, Gordan Lauc, Vlatka Zoldoš
Background: Many genome- and epigenome-wide association studies (GWAS and EWAS) and studies of promoter methylation of candidate genes for inflammatory bowel disease (IBD) have demonstrated significant associations between genetic and epigenetic changes and IBD. Independent GWA studies have identified genetic variants in the BACH2 , IL6ST , LAMB1 , IKZF1 , and MGAT3 loci to be associated with both IBD and immunoglobulin G (IgG) glycosylation. Methods: Using bisulfite pyrosequencing, we analyzed CpG methylation in promoter regions of these five genes from peripheral blood of several hundred IBD patients and healthy controls (HCs) from two independent cohorts, respectively...
2018: Clinical Epigenetics
Susan Branford, Paul Wang, David T Yeung, Daniel Thomson, Adrian Purins, Carol Wadham, Nur Hezrin Shahrin, Justine E Marum, Nathalie Nataren, Wendy T Parker, Joel Geoghegan, Jinghua Feng, Naranie Shanmuganathan, Martin C Mueller, Christian Dietz, Doris Stangl, Zoe Donaldson, Haley Altamura, Jasmina Georgievski, Jodi Braley, Anna Brown, Christopher Hahn, Ieuan Walker, Soo-Hyun Kim, Soo-Young Choi, Sa-Hee Park, Dong-Wook Kim, Deborah L White, Agnes S M Yong, David M Ross, Hamish S Scott, Andreas W Schreiber, Timothy P Hughes
Genomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole exome sequencing, copy number variation and/or RNA-Seq for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six chronic phase patients with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15/27 patients (56%) with subsequent BC or poor outcome and in 3/19 optimal responders (16%), P=.007. Frequently mutated genes at diagnosis were ASXL1 , IKZF1 and RUNX1 The methyltransferase SETD1B was a novel recurrently mutated gene...
July 2, 2018: Blood
M Kathiravan, Minu Singh, Prateek Bhatia, Amita Trehan, Neelam Varma, Manupdesh Singh Sachdeva, Deepak Bansal, Richa Jain, Shano Naseem
Considering conflicting data on CDKN2A/B deletion in ALL, this study to assess its prognostic significance as an independent marker in a total of 96 pediatric B and T-ALL cases was planned. The overall frequency of CDKN2A/B deletion was 44% (n = 43) with 36% (30/83) in B-ALL and 100% (13/13) in T-ALL. CDKN2A/B deletion was significantly associated with high WBC count (p = .002) and National Cancer Institute risk (p = .01) in B-ALL. Importantly, CDKN2A/B deletion cases had poor EFS of 42% at 28 months compared to EFS of 90% in rest (p = ...
July 3, 2018: Leukemia & Lymphoma
James C Chen, Rolando Perez-Lorenzo, Yvonne M Saenger, Charles G Drake, Angela M Christiano
Immunotherapies are some of the most promising emergent treatments for several cancers, yet there remains a majority of patients who do not benefit from them due to immune-resistant tumors. One avenue for enhancing treatment for these patients is by converting these tumors to an immunoreactive state, thereby restoring treatment efficacy. By leveraging regulatory networks we previously characterized in autoimmunity, here we show that overexpression of the master regulator IKZF1 leads to enhanced immune infiltrate recruitment and tumor sensitivity to PD1 and CTLA4 inhibitors in several tumors that normally lack IKZF1 expression...
July 25, 2018: Cell Systems
Junichi Hashiguchi, Masahiro Onozawa, Satoshi Oguri, Shinichi Fujisawa, Masahisa Tsuji, Kohei Okada, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Takeshi Kondo, Chikara Shimizu, Takanori Teshima
Intragenic deletion of IKZF1 is a recurrent genomic alteration in acute lymphoblastic leukemia. The deletions are mediated by illegitimate variable(diversity)joining recombination via cryptic recombination signal sequences (RSSs). We developed a fluorescence in situ hybridization (FISH) probe set that can detect any type of IKZF1 deletion, including the commonly deleted exon 4 to 7 region. The probe set consists of a designed probe for the commonly deleted region (Cy3; red) and a bacterial artificial chromosomes clone probe for detecting the 3' flanking region (Spectrum Green)...
July 2018: Journal of Molecular Diagnostics: JMD
Ailing Liu, Shirong Li, Vera Donnenberg, Jing Fu, Susanne M Gollin, Huihui Ma, Caisheng Lu, Donna B Stolz, Markus Y Mapara, Sara A Monaghan, Suzanne Lentzsch
The immunomodulatory drugs, lenalidomide and pomalidomide yield high response rates in multiple myeloma patients, but are associated with a high rate of thrombocytopenia and increased risk of secondary hematologic malignancies. Here, we demonstrate that the immunomodulatory drugs induce self-renewal of hematopoietic progenitors and upregulate megakaryocytic colonies by inhibiting apoptosis and increasing proliferation of early megakaryocytic progenitors via down-regulation of IKZF1. In this process, the immunomodulatory drugs degrade IKZF1 and subsequently down-regulate its binding partner, GATA1...
June 28, 2018: Haematologica
Ajinkya Patil, Mark Manzano, Eva Gottwein
Primary effusion lymphoma (PEL) is an aggressive cancer with few treatment options. The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide have recently been shown to kill PEL cell lines and lenalidomide is in clinical trials against PEL. IMiDs bind to the CRL4CRBN E3 ubiquitin ligase complex, leading to the acquisition of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), casein kinase 1 alpha (CK1α) and zinc finger protein 91 (ZFP91) as neosubstrates. IMiDs are effective against multiple myeloma, due to degradation of IKZF1 and IKZF3 and the consequent loss of interferon regulatory factor 4 (IRF4) and MYC expression...
June 28, 2018: Blood
Peter H Schafer, Ying Ye, Lei Wu, Jolanta Kosek, Garth Ringheim, Zhihong Yang, Liangang Liu, Michael Thomas, Maria Palmisano, Rajesh Chopra
OBJECTIVES: IKZF1 and IKZF3 ( encoding transcription factors Ikaros and Aiolos) are susceptibility loci for systemic lupus erythematosus (SLE). The pharmacology of iberdomide (CC-220), a cereblon ( CRBN ) modulator targeting Ikaros and Aiolos, was studied in SLE patient cells and in a phase 1 healthy volunteer study. METHODS: CRBN , IKZF1 and IKZF3 gene expression was measured in peripheral blood mononuclear cells (PBMC) from patients with SLE and healthy volunteers...
June 26, 2018: Annals of the Rheumatic Diseases
Shanhao Tang, Hongjie Shen, Changju Qu, Haiping Dai, Xiaming Zhu, Shengli Xue, Zixuan Ding, Jing Lu, Depei Wu, Xiaowen Tang
To investigate the prognosis of patients with adult B-cell acute lymphoblastic leukemia (B-ALL) with Ikaros family zinc-finger 1 (IKZF1) mutation and determine the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in improving the clinical outcome, we detected the IKZF1 mutation and BCR-ABL fusion gene at diagnosis in the bone marrow of 164 adult patients with B-ALL, and analyzed the clinical data of these patients retrospectively. Our analysis showed that grade III-IV acute graft-versus-host disease and IKZF1 mutation in the transplantation group and age and IKZF1 mutation in the non-transplantation group were independent factors for poor prognosis by univariate and multivariate analyses...
June 25, 2018: Bone Marrow Transplantation
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