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https://www.readbyqxmd.com/read/28087699/activation-of-c-abl-kinase-potentiates-the-anti-myeloma-drug-lenalidomide-by-promoting-dda1-recruitment-to-the-crl4-ubiquitin-ligase
#1
Shaobing Gao, Chenlu Geng, Tianyu Song, Xuanru Lin, Jiye Liu, Zhen Cai, Yong Cang
Cullin Ring Ligase 4 (CRL4), a complex of Cul4 and DDB1, regulates cell cycle, DNA damage repair, and chromatin replication by targeting a variety of substrates for ubiquitination. CRL4 is also hijacked by viral proteins or thalidomide-derived compounds to degrade host restriction factors. Here we report that the c-Abl non-receptor kinase phosphorylates DDB1 at residue Y316 to recruit a small regulatory protein DDA1, leading to increased substrate ubiquitination. Pharmacological inhibition or genetic ablation of the Abl-DDB1-DDA1 axis decreases the ubiquitination of CRL4 substrates, including IKZF1 and IKZF3 in lenalidomide-treated multiple myeloma cells...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28052520/ikaros-expression-in-distinct-bone-marrow-cell-populations-as-a-candidate-biomarker-for-outcome-with-lenalidomide-dexamethasone-therapy-in-multiple-myeloma
#2
Arnold Bolomsky, Wolfgang Hübl, Stefano Spada, Ercan Müldür, Karin Schlangen, Daniel Heintel, Alberto Rocci, Adalbert Weißmann, Veronique Fritz, Martin Willheim, Niklas Zojer, Antonio Palumbo, Heinz Ludwig
Immunomodulatory drugs (IMiDs) are a cornerstone in the treatment of multiple myeloma (MM), but specific markers to predict outcome are still missing. Recent work pointed to a prognostic role for IMiD target genes (e.g. CRBN). Moreover, indirect activity of IMiDs on immune cells correlated with outcome, raising the possibility that cell populations in the bone marrow (BM) microenvironment could serve as biomarkers. We therefore analysed gene expression levels of six IMiD target genes in whole BM samples of 44 myeloma patients treated with lenalidomide-dexamethasone...
January 4, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28033648/characterisation-of-the-genomic-landscape-of-crlf2-rearranged-acute-lymphoblastic-leukemia
#3
Lisa J Russell, Lisa Jones, Amir Enshaei, Stefano Tonin, Sarra L Ryan, Jeyanthy Eswaran, Sirintra Nakjang, Elli Papaemmanuil, Jose M C Tubio, Adele K Fielding, Ajay Vora, Peter J Campbell, Anthony V Moorman, Christine J Harrison
Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We aimed to determine the clinical and genetic landscape of those with IGH-CRLF2 or P2RY8-CRLF2 (CRLF2-r) using multiple genomic approaches. Clinical and demographic features of CRLF2-r patients were characteristic of B-ALL. Patients with IGH-CRLF2 were older (14 y vs. 4 y, P < .001), while the incidence of CRLF2-r among Down syndrome patients was high (50/161, 31%)...
December 29, 2016: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28030830/ikaros-regulation-of-the-bcl6-bach2-axis-and-its-clinical-relevance-in-acute-lymphoblastic-leukemia
#4
Zheng Ge, Xilian Zhou, Yan Gu, Qi Han, Jianyong Li, Baoan Chen, Qinyu Ge, Elanora Dovat, Jonathon L Payne, Tianyu Sun, Chunhua Song, Sinisa Dovat
B-Cell CLL/Lymphoma 6 (BCL6) is a proto-oncogene that is highly expressed in acute lymphoblastic leukemia (ALL). BTB and CNC Homology 1 Basic Leucine Zipper Transcription Factor 2 (BACH2) is a suppressor of transcription. The BACH2-BCL6 balance controls selection at the pre-B cell receptor checkpoint by regulating p53 expression. However, the underlying mechanism and the clinical relevance of the BCL6/BACH2 axis are unknown. Here, we found that Ikaros, a tumor suppressor encoded by IKZF1, directly binds to both the BCL6 and BACH2 promoters where it suppresses BCL6 and promotes BACH2 expression in B-cell ALL (B-ALL) cells...
December 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/28028022/multiple-myeloma-cells-capacity-to-decompose-h2o2-determines-lenalidomide-sensitivity
#5
Sinto Sebastian, Yuan X Zhu, Esteban Braggio, Chang-Xin Shi, Sonali C Panchabhai, Scott A Van Wier, Greg J Ahmann, Marta Chesi, P Leif Bergsagel, A Keith Stewart, Rafael Fonseca
Lenalidomide is an immunomodulatory drug (IMiDs) with clinical efficacy in multiple myeloma (MM) and other late B-cell neoplasms. Although cereblon (CRBN) is an essential requirement for IMiD action, the complete molecular and biochemical mechanisms responsible for lenalidomide-mediated sensitivity or resistance remain unknown. Here, we report that IMiDs work primarily via inhibition of peroxidase-mediated intracellular H2O2 decomposition in MM cells. MM cells with lower H2O2-decomposition capacity were more vulnerable to lenalidomide-induced H2O2 accumulation and associated cytotoxicity...
December 27, 2016: Blood
https://www.readbyqxmd.com/read/28017969/ikzf1-expression-is-a-prognostic-marker-in-newly-diagnosed-standard-risk-multiple-myeloma-treated-with-lenalidomide-and-intensive-chemotherapy-a-study-of-the-german-myeloma-study-group-dsmm
#6
J Krönke, F Kuchenbauer, M Kull, V Teleanu, L Bullinger, D Bunjes, A Greiner, S Kolmus, S Köpff, M Schreder, L-O Mügge, C Straka, M Engelhardt, H Döhner, H Einsele, F Bassermann, R Bargou, S Knop, C Langer
Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth-inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSG mRNA expression levels in pretreatment plasma cells from sixty patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial...
December 26, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27983717/evaluation-of-methylation-biomarkers-for-detection-of-circulating-tumor-dna-and-application-to-colorectal-cancer
#7
Susan M Mitchell, Thu Ho, Glenn S Brown, Rohan T Baker, Melissa L Thomas, Aidan McEvoy, Zheng-Zhou Xu, Jason P Ross, Trevor J Lockett, Graeme P Young, Lawrence C LaPointe, Susanne K Pedersen, Peter L Molloy
Solid tumors shed DNA into circulation, and there is growing evidence that the detection of circulating tumor DNA (ctDNA) has broad clinical utility, including monitoring of disease, prognosis, response to chemotherapy and tracking tumor heterogeneity. The appearance of ctDNA in the circulating cell-free DNA (ccfDNA) isolated from plasma or serum is commonly detected by identifying tumor-specific features such as insertions, deletions, mutations and/or aberrant methylation. Methylation is a normal cell regulatory event, and since the majority of ccfDNA is derived from white blood cells (WBC), it is important that tumour-specific DNA methylation markers show rare to no methylation events in WBC DNA...
December 15, 2016: Genes
https://www.readbyqxmd.com/read/27979924/tumor-suppressors-btg1-and-ikzf1-cooperate-during-mouse-leukemia-development-and-increase-relapse-risk-in-b-cell-precursor-acute-lymphoblastic-leukemia-patients
#8
Blanca Scheijen, Judith M Boer, Rene' Marke, Esther Tijchon, Dorette van Ingen Schenau, Esme' Waanders, Liesbeth van Emst, Laurens T van der Meer, Rob Pieters, Gabriele Escherich, Martin A Horstmann, Edwin Sonneveld, Nicola Venn, Rosemary Sutton, Luciano Dalla-Pozza, Roland P Kuiper, Peter M Hoogerbrugge, Monique L den Boer, Frank N van Leeuwen
Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of IKZF1 deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single copy losses of BTG1 were significantly enriched in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia (P=0...
December 15, 2016: Haematologica
https://www.readbyqxmd.com/read/27957801/genomic-characterization-of-pediatric-b-lymphoblastic-lymphoma-and-b-lymphoblastic-leukemia-using-formalin-fixed-tissues
#9
Julia A Meyer, Delu Zhou, Clinton C Mason, Jonathan M Downie, Vladimir Rodic, Minnie Abromowitch, Birte Wistinghausen, Amanda M Termuhlen, Anne L Angiolillo, Sherrie L Perkins, Phillip Barnette, Joshua D Schiffman, Rodney R Miles
BACKGROUND: Recurrent genomic changes in B-lymphoblastic leukemia (B-ALL) identified by genome-wide single-nucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, B-lymphoblastic lymphoma (B-LBL), is limited by the low incidence and lack of fresh tissue for genomic testing. PROCEDURE: We used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalin-fixed paraffin-embedded pediatric B-LBL (n = 23) and B-ALL (n = 55)...
December 13, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27939403/abnormal-hematopoiesis-and-autoimmunity-in-human-subjects-with-germline-ikzf1-mutations
#10
Akihiro Hoshino, Satoshi Okada, Kenichi Yoshida, Naonori Nishida, Yusuke Okuno, Hiroo Ueno, Motoi Yamashita, Tsubasa Okano, Miyuki Tsumura, Shiho Nishimura, Sonoko Sakata, Masao Kobayashi, Haruna Nakamura, Junji Kamizono, Kanako Mitsui-Sekinaka, Takuya Ichimura, Shouichi Ohga, Yozo Nakazawa, Masatoshi Takagi, Kohsuke Imai, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Seishi Ogawa, Seiji Kojima, Shigeaki Nonoyama, Tomohiro Morio, Hirokazu Kanegane
BACKGROUND: Ikaros, which is encoded by IKZF1, is a transcriptional factor that play a critical role in hematopoiesis. Somatic IKZF1 alterations are known to be involved in the pathogenesis of leukemia in human subjects. Recently, immunodeficiency caused by germline IKZF1 mutation has been described. OBJECTIVE: We sought to describe the clinical and immunologic phenotypes of Japanese patients with heterozygous IKZF1 mutations. METHODS: We performed whole-exome sequencing in patients from a dysgammaglobulinemia or autoimmune disease cohort and used a candidate gene approach in 4 patients...
December 1, 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27899802/genomic-and-transcriptional-landscape-of-p2ry8-crlf2-positive-childhood-acute-lymphoblastic-leukemia
#11
C Vesely, C Frech, C Eckert, G Cario, A Mecklenbräuker, U Zur Stadt, K Nebral, F Kraler, S Fischer, A Attarbaschi, M Schuster, C Bock, H Cavé, A von Stackelberg, M Schrappe, M A Horstmann, G Mann, O A Haas, R Panzer-Grümayer
Children with P2RY8-CRLF2-positive ALL have an increased relapse risk. Their mutational and transcriptional landscape as well as the respective patterns at relapse remains largely elusive. We therefore performed an integrated analysis of whole-exome and RNA-sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway activating mutations in 76% of cases at diagnosis and virtually all relapses...
November 30, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27894077/tyrosine-kinase-fusion-genes-in-pediatric-bcr-abl1-like-acute-lymphoblastic-leukemia
#12
Judith M Boer, Elisabeth M P Steeghs, João R M Marchante, Aurélie Boeree, James J Beaudoin, H Berna Beverloo, Roland P Kuiper, Gabriele Escherich, Vincent H J van der Velden, C Ellen van der Schoot, Hester A de Groot-Kruseman, Rob Pieters, Monique L den Boer
Approximately 15% of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by gene expression similar to that of BCR-ABL1-positive disease and unfavorable prognosis. This BCR-ABL1-like subtype shows a high frequency of B-cell development gene aberrations and tyrosine kinase-activating lesions. To evaluate the clinical significance of tyrosine kinase gene fusions in children with BCP-ALL, we studied the frequency of recently identified tyrosine kinase fusions, associated genetic features, and prognosis in a representative Dutch/German cohort...
November 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/27890933/preclinical-activity-of-cpi-0610-a-novel-small-molecule-bromodomain-and-extra-terminal-protein-inhibitor-in-the-therapy-of-multiple-myeloma
#13
K T Siu, J Ramachandran, A J Yee, H Eda, L Santo, C Panaroni, J A Mertz, R J Sims Iii, M R Cooper, N Raje
Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic cancers. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through the suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the antitumor activity of BET inhibitors but is less well understood. Here we examined the therapeutic potential of CPI-0610, a potent BET inhibitor currently undergoing phase I clinical testing, in multiple myeloma (MM)...
January 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27885263/targeting-high-dynamin-2-dnm2-expression-by-restoring-ikaros-function-in-acute-lymphoblastic-leukemia
#14
Zheng Ge, Yan Gu, Qi Han, Gang Zhao, Min Li, Jianyong Li, Baoan Chen, Tianyu Sun, Sinisa Dovat, Robert Peter Gale, Chunhua Song
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...
November 25, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27874290/impact-of-clinical-factors-on-outcome-of-leukemia-patients-with-tls-erg-fusion-gene
#15
Jing Pan, Yang Zhang, Yan-Li Zhao, Jun-Fang Yang, Jian-Ping Zhang, Hong-Xing Liu, Tong Wu, Chun-Rong Tong
We report the clinical features and outcome of 22 TLS-ERG(+ )leukemia patients (20 AML and 2 B-ALL). TLS-ERG was tightly associated with extramedullary disease (EMD), complex chromosome abnormalities, and high risk gene mutations including IKZF1, WT1, TET2, NOTCH2, and PHF6. The 6-month leukemia free survival (LFS) with and without EMD was 75% and 83.3% (p = .017). 11/20 AML patients received allogeneic hematopoietic stem cell transplantation (HCT). The 1-year overall survival (OS) in non-HCT and HCT group was 62...
November 22, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27865806/ikaros-exploiting-and-targeting-the-hematopoietic-stem-cell-niche-in%C3%A2-b-progenitor-acute-lymphoblastic-leukemia
#16
REVIEW
Michelle L Churchman, Charles G Mullighan
Genetic alterations of IKZF1 encoding the lymphoid transcription factor IKAROS are a hallmark of high-risk B-progenitor acute lymphoblastic leukemia (ALL), such as BCR-ABL1-positive (Ph+) and Ph-like ALL, and are associated with poor outcome even in the era of contemporary chemotherapy incorporating tyrosine kinase inhibitors. Recent experimental mouse modeling of B-progenitor ALL has shown that IKZF1 alterations have multiple effects, including arresting differentiation, skewing lineage of leukemia from myeloid to lymphoid, and, in Ph+ leukemia, conferring resistance to tyrosine kinase inhibitor (TKI) therapy without abrogating ABL1 inhibition...
February 2017: Experimental Hematology
https://www.readbyqxmd.com/read/27829444/potential-molecular-characteristics-in-situ-in-response-to-repetitive-uvb-irradiation
#17
Wenqi Chen, Jinhai Zhang
BACKGROUND: To identify molecular characteristics in situ in response to repetitive UVB (ultraviolet-B) irradiation. METHODS: Microarray data from the Gene Expression Omnibus were re-analyzed to identify DEGs (differentially expressed genes) between UVB-irradiated and non-irradiated skin biopsies. Enrichment and annotation analyses were performed respectively using DAVID, and TSGene and TAG databases. PPIs (protein-protein interactions) were analyzed using STRING, and miRNAs (microRNAs) and TFs (transcription factors) were predicted separately by miRNA-related databases and ENCODE...
November 10, 2016: Diagnostic Pathology
https://www.readbyqxmd.com/read/27815723/prognostic-significance-of-ikzf1-deletion-in-adult-b-cell-acute-lymphoblastic-leukemia-a-meta-analysis
#18
Wanhua Zhang, Pu Kuang, He Li, Fengjuan Wang, Yu Wang
The IKAROS family zinc finger 1 (IKZF1) gene is frequently altered in adults with B cell acute lymphoblastic leukemia (ALL). Although many studies have indicated that IKZF1 alterations might be associated with poor outcomes in adults with ALL, the results remain controversial. A previous meta-analysis demonstrated the negative prognostic significance of IKZF1 deletion in ALL. However, most of the included studies (14 out of 15) were conducted in pediatric patients with ALL, and age was identified as a significant source of heterogeneity...
November 4, 2016: Annals of Hematology
https://www.readbyqxmd.com/read/27756164/biallelic-loss-of-cdkn2a-is-associated-with-poor-response-to-treatment-in-pediatric-acute-lymphoblastic-leukemia
#19
Marcin Braun, Agata Pastorczak, Wojciech Fendler, Joanna Madzio, Bartlomiej Tomasik, Joanna Taha, Marta Bielska, Lukasz Sedek, Tomasz Szczepanski, Michal Matysiak, Katarzyna Derwich, Monika Lejman, Jerzy Kowalczyk, Bernarda Kazanowska, Wanda Badowska, Jan Styczynski, Nina Irga-Jaworska, Joanna Trelinska, Beata Zalewska-Szewczyk, Filip Pierlejewski, Iwona Wlodarska, Wojciech Młynarski
The inactivation of tumor suppressor genes located within 9p21 locus (CDKN2A, CDKN2B) occurs in up to 30% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but its independent prognostic significance remains controversial. In order to investigate the prognostic impact of deletions and promoter methylation within 9p21, 641 children with newly diagnosed BCP-ALL using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) were investigated. A total of 169 (26.4%) microdeletions in 9p21 were detected, of which 71 were homozygous...
October 18, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27726312/a-cross-sectional-study-comparing-a-blood-test-for-methylated-bcat1-and-ikzf1-tumor-derived-dna-with-cea-for-detection-of-recurrent-colorectal-cancer
#20
Graeme P Young, Susanne K Pedersen, Scott Mansfield, David H Murray, Rohan T Baker, Philippa Rabbitt, Susan Byrne, Libby Bambacas, Paul Hollington, Erin L Symonds
Recurrence will develop in 30-50% of colorectal cancer (CRC) cases despite apparent clearance following treatment. Carcinoembryonic antigen (CEA) is the only guideline-recommended blood test for monitoring cases for recurrence, but its sensitivity and specificity are suboptimal. This observational study compared a novel 2-gene (methylated BCAT1 and IKZF1 DNA) blood test with CEA for detection of recurrent CRC. We conducted a paired comparison of the BCAT1/IKZF1 test with CEA (cut-off 5 ng/mL) in blood from patients in remission after treatment for primary CRC and undergoing surveillance...
October 11, 2016: Cancer Medicine
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