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1
Pallarès, Victor, Montserrat Hoyos, M. Chillón, Eva Barragán, M. Prieto Conde, Marta Llop, Aïda Falgàs, et al. "Focal Adhesion Genes Refine the Intermediate-Risk Cytogenetic Classification of Acute Myeloid Leukemia." Cancers 10, no. 11 (November 13, 2018): 436. http://dx.doi.org/10.3390/cancers10110436.
Abstract:
In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate with metastatic dissemination in solid tumors and poor prognosis. However, their role in haematological malignancies has been scarcely studied. We hypothesized that PTK2/FAK, PTK2B/PYK2, LYN or SRC could be new prognostic markers in IR-AML. We assessed PTK2, PTK2B, LYN and SRC gene expression in a cohort of 324 patients, adults up to the age of 70, classified in the IR-AML cytogenetic group. Univariate and multivariate analyses showed that PTK2B, LYN and PTK2 gene expression are independent prognostic factors in IR-AML patients. PTK2B and LYN identify a patient subgroup with good prognosis within the cohort with non-favorable FLT3/NPM1 combined mutations. In contrast, PTK2 identifies a patient subgroup with poor prognosis within the worst prognosis cohort who display non-favorable FLT3/NPM1 combined mutations and underexpression of PTK2B or LYN. The combined use of these markers can refine the highly heterogeneous intermediate-risk subgroup of AML patients, and allow the development of risk-adapted post-remission chemotherapy protocols to improve their response to treatment.
2
Porter, Tyrel, Miguel Mayol del Valle, and Lilia Kucheryavykh. "Ethnicity-Based Variations in Focal Adhesion Kinase Signaling in Glioblastoma Gene Expression: A Study of the Puerto Rican Hispanic Population." International Journal of Molecular Sciences 25, no. 9 (May 1, 2024): 4947. http://dx.doi.org/10.3390/ijms25094947.
Abstract:
Glioblastoma (GBM), an aggressive form of brain cancer, has a higher incidence in non-Hispanics when compared to the US Hispanic population. Using data from RT-PCR analysis of 21 GBM tissue from Hispanic patients in Puerto Rico, we identified significant correlations in the gene expression of focal adhesion kinase and proline-rich tyrosine kinase (PTK2 and PTK2B) with NGFR (nerve growth factor receptor), PDGFRB (platelet-derived growth factor receptor B), EGFR (epithelial growth factor receptor), and CXCR1 (C-X-C motif chemokine receptor 1). This study further explores these correlations found in gene expression while accounting for sex and ethnicity. Statistically significant (p < 0.05) correlations with an r value > ±0.7 were subsequently contrasted with mRNA expression data acquired from cBioPortal for 323 GBM specimens. Significant correlations in Puerto Rican male patients were found between PTK2 and PTK2B, NGFR, PDGFRB, EGFR, and CXCR1, which did not arise in non-Hispanic male patient data. The data for Puerto Rican female patients showed correlations in PTK2 with PTK2B, NGFR, PDGFRB, and EGFR, all of which did not appear in the data for non-Hispanic female patients. The data acquired from cBioPortal for non-Puerto Rican Hispanic patients supported the correlations found in the Puerto Rican population for both sexes. Our findings reveal distinct correlations in gene expression patterns, particularly involving PTK2, PTK2B, NGFR, PDGFRB, and EGFR among Puerto Rican Hispanic patients when compared to non-Hispanic counterparts.
3
Chen, Cui, Zhen Tao, Ya Li, Jie Li, and Yang Xu. "MicroRNA214 expression inhibits HCC cell proliferation through PTK2b/ Pyk2." Cellular and Molecular Biology 68, no. 1 (May 22, 2022): 20–25. http://dx.doi.org/10.14715/cmb/2022.68.1.4.
Abstract:
MicroRNAs (miRNAs/miRs) are crucial regulatory molecules that act as the most significantly downregulated microRNAs in hepatocellular carcinoma (HCC). PTK2b/Pyk2 is a non-receptor protein tyrosine kinase, which plays an important role in the development and metastasis of cancer. In this study, we explored the expression level and functional relationship between MicroRNA-214 (miR-214) and PTK2b/ Pyk2 in liver cancer cells. For this purpose, we analyzed the expression of miR-214 and PTK2b/Pyk2 in 38 cases of HCC and paired non-neoplastic tissue specimens using real-time PCR. MTT, cell cycle and construct recombinant plasmids analysis were used to explore the effects of miR-214 and PTK2b/Pyk2 on liver cancer cell proliferation. Results showed that the expression level of mir-214 in liver cancer tissues and liver cancer cell lines was significantly lower than that in normal tissues and cells, while the expression of PTK2b/Pyk2 was significantly increased. The overexpression of mir-214 or inhibition PTK2b/Pyk2 inhibited the proliferation of HCC cells. This research showed that mir-214 has an inhibitory effect on liver cancer through the expression of PTK2b/Pyk2.
4
Luo, Jinping, Lynda K. McGinnis, Carol Carlton, Hilary E. Beggs, and William H. Kinsey. "PTK2b function during fertilization of the mouse oocyte." Biochemical and Biophysical Research Communications 450, no. 3 (August 2014): 1212–17. http://dx.doi.org/10.1016/j.bbrc.2014.03.083.
5
N'Songo, Aurelie, Minerva M. Carrasquillo, Xue Wang, Jeremy D. Burgess, Thuy Nguyen, Yan W. Asmann, Daniel J. Serie, et al. "African American exome sequencing identifies potential risk variants at Alzheimer disease loci." Neurology Genetics 3, no. 2 (April 2017): e141. http://dx.doi.org/10.1212/nxg.0000000000000141.
Abstract:
Objective:In African Americans, we sought to systematically identify coding Alzheimer disease (AD) risk variants at the previously reported AD genome-wide association study (GWAS) loci genes.Methods:We identified coding variants within genes at the 20 published AD GWAS loci by whole-exome sequencing of 238 African American participants, validated these in 300 additional participants, and tested their association with AD risk in the combined cohort of 538 and with memory endophenotypes in 319 participants.Results:Two ABCA7 missense variants (rs3764647 and rs3752239) demonstrated significant association with AD risk. Variants in MS4A6A, PTK2B, and ZCWPW1 showed significant gene-based association. In addition, coding variants in ZCWPW1 (rs6465770) and NME8 (rs10250905 and rs62001869) showed association with memory endophenotypes.Conclusions:Our findings support a role for ABCA7 missense variants in conferring AD risk in African Americans, highlight allelic heterogeneity at this locus, suggest the presence of AD-risk variants in MS4A6A, PTK2B, and ZCWPW1, nominate additional variants that may modulate cognition, and importantly provide a thorough screen of coding variants at AD GWAS loci that can guide future studies in this population.
6
Giralt, Albert, Benoit de Pins, Carmen Cifuentes-Díaz, Laura López-Molina, Amel Thamila Farah, Marion Tible, Vincent Deramecourt, et al. "PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease." Experimental Neurology 307 (September 2018): 62–73. http://dx.doi.org/10.1016/j.expneurol.2018.05.020.
7
Ni, Bin, Jared S. Farrar, Shanshan Chen, Joseph C. Lownik, and Francesco S. Celi. "A novel role for PTK2B in cultured beige adipocyte differentiation." Biochemical and Biophysical Research Communications 501, no. 4 (July 2018): 851–57. http://dx.doi.org/10.1016/j.bbrc.2018.05.021.
8
Chu, Weiwei, Lili Guan, Dihua Huang, Yuezhong Ren, and Yan Zhou. "Lovastatin exerts protective effects on endothelial cells via upregulation of PTK2B." Experimental and Therapeutic Medicine 12, no. 3 (July 26, 2016): 1741–49. http://dx.doi.org/10.3892/etm.2016.3547.
9
Piaggio, Francesca, Veronica Tozzo, Cinzia Bernardi, Michela Croce, Roberto Puzone, Silvia Viaggi, Serena Patrone, et al. "Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma." Cancers 11, no. 11 (October 30, 2019): 1688. http://dx.doi.org/10.3390/cancers11111688.
Abstract:
Background: Uveal melanoma (UM), a rare cancer of the eye, is characterized by initiating mutations in the genes G-protein subunit alpha Q (GNAQ), G-protein subunit alpha 11 (GNA11), cysteinyl leukotriene receptor 2 (CYSLTR2), and phospholipase C beta 4 (PLCB4) and by metastasis-promoting mutations in the genes splicing factor 3B1 (SF3B1), serine and arginine rich splicing factor 2 (SRSF2), and BRCA1-associated protein 1 (BAP1). Here, we tested the hypothesis that additional mutations, though occurring in only a few cases (“secondary drivers”), might influence tumor development. Methods: We analyzed all the 4125 mutations detected in exome sequencing datasets, comprising a total of 139 Ums, and tested the enrichment of secondary drivers in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that also contained the initiating mutations. We searched for additional mutations in the putative secondary driver gene protein tyrosine kinase 2 beta (PTK2B) and we developed new mutational signatures that explain the mutational pattern observed in UM. Results: Secondary drivers were significantly enriched in KEGG pathways that also contained GNAQ and GNA11, such as the calcium-signaling pathway. Many of the secondary drivers were known cancer driver genes and were strongly associated with metastasis and survival. We identified additional mutations in PTK2B. Sparse dictionary learning allowed for the identification of mutational signatures specific for UM. Conclusions: A considerable part of rare mutations that occur in addition to known driver mutations are likely to affect tumor development and progression.
10
Liu, Zhen, Kai-Min Hao, Hao-Yu Wang, and Wen-Xiu Qi. "Histone deacetylase-6 modulates amyloid beta-induced cognitive dysfunction rats by regulating PTK2B." NeuroReport 31, no. 10 (May 21, 2020): 754–61. http://dx.doi.org/10.1097/wnr.0000000000001481.
11
Terao, Chikashi, Hajime Yoshifuji, Takayoshi Matsumura, Taeko K. Naruse, Tomonori Ishii, Yoshikazu Nakaoka, Yohei Kirino, et al. "Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis." Proceedings of the National Academy of Sciences 115, no. 51 (November 29, 2018): 13045–50. http://dx.doi.org/10.1073/pnas.1808850115.
Abstract:
Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B, LILRA3/LILRB2, DUSP22, and KLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6/FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B. Rs103294 risk allele in LILRA3/LILRB2 is known to be a tagging SNP for the deletion of LILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P = 1.2 × 10−3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 × 10−5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.
12
Tang, Nanyun, Kristin Leskoske, Krystine Garcia-Mansfield, Ritin Sharma, Hannah Tolson, Patrick Pirrotte, and Michael Berens. "CSIG-31. MULTI-OMICS TO EDGE INTO PRECISION MEDICINE FOR DIPG." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi40. http://dx.doi.org/10.1093/neuonc/noab196.157.
Abstract:
Abstract DIPG is an incurable pediatric brain tumor with 80% of patients harboring H3F3A (H3.3) mutation that substitutes methionine for lysine at position 27 (K27M), resulting in global depletion of H3.3K27 me3 (trimethylation). These histone mutations modify the epigenome and alter oncogenic transcription, causing oncogenic insults to progenitor cells in early neurodevelopment (1). To determine the reprogramming pathways in the cell context of H3.3K27M tumors, we conducted LC-MS based proteomic and phosphoproteomic analysis on seven patient-derived DIPG cell lines. Three normal neuronal stem cell lines were included as non-tumor brain cells for comparison. Pathway analysis identified 29 pathways that are significantly altered in DIPG compared to normal brain cells at both the protein abundance and phosphosite level. Notably, AKT and MAPK associated PI3K signaling, VEGF signaling, mTOR signaling, and HIF1a signaling were differentially active in H3.3K27M tumors compared to healthy control cell lines. We saw significantly higher activity of multiple kinases involved in axon guidance and cytoskeletal remodeling in DIPG, such as PTK2B, DYRK2, TTBK2 and MARK2. This is the first time to report an increased abundance and kinase activity of PYK2 protein (coded by PTK2B), a close homologue of FAK and its associated signaling in DIPG. PYK2 has been proposed to act in concert with Src to link Gi- or Gq-coupled receptors with the mitogen-activated protein (MAP) kinase signaling pathway (2). Because of the shared signaling across kinase pathways, targeting activated PYK2 in DIPG may complement inhibitors of other dysregulated signaling networks in DIPG such as MAPK2, VEGFR, PI3K and Src. Our data also found that IL13RA2 was upregulated in DIPG. We conclude that for H3 K27M DIPG tumors, campaigns to target PYK2, MAPK2, VEGFR, PI3K, Src and IL13Ra2 using small molecules that traverse the blood brain barrier loom as promising opportunities for drug development.
13
Polis, Baruh, and Hava Gil-Henn. "Commentary on Giralt et al.: PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease." Experimental Neurology 311 (January 2019): 313–17. http://dx.doi.org/10.1016/j.expneurol.2018.08.011.
14
Cong, Yanyan, Haibo Wu, Xuejiao Bian, Qin Xie, Qifeng Lyu, Junqi Cui, Lun Suo, and Yanping Kuang. "Ptk2b deletion improves mice folliculogenesis and fecundity via inhibiting follicle loss mediated by Erk pathway." Journal of Cellular Physiology 236, no. 2 (July 2020): 1043–53. http://dx.doi.org/10.1002/jcp.29914.
15
Kadoba, K., R. Watanabe, T. Iwasaki, K. Kitagori, S. Akizuki, K. Murakami, R. Nakashima, et al. "POS0345 CLINICOGENETIC STUDY OF FIVE NOVEL SUSCEPTIBILITY LOCI FOR TAKAYASU ARTERITIS: SUSCEPTIBILITY LOCI IN THE IL12B AND PTK2B REGION, BUT NOT THE LILRA3, DUSP22, KLHL33 REGIONS, ARE ASSOCIATED WITH VASCULAR DAMAGE IN TAKAYASU ARTERITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 401.2–402. http://dx.doi.org/10.1136/annrheumdis-2021-eular.289.
Abstract:
Background:We have previously identified single nucleotide polymorphism (SNP) rs6871626 in IL12B, rs103294 in LILRA3, rs17133698 in DUSP22, rs2322599 in PTK2B, and rs1713450 in KLHL33 as non-HLA susceptibility loci in Takayasu arteritis (TAK) [1, 2]. However, the association of these SNPs with clinical features has scarcely investigated.Objectives:In this study, we aimed to examine how these SNPs contribute to clinical features and vascular damage in TAK.Methods:We enrolled 99 TAK patients who were enrolled in our previous genome-wide association study (GWAS) [2]. To assess vascular damage, Takayasu Arteritis Damage Score (TADS) and Vasculitis Damage Index (VDI) were measured at the last visit before November 2020. As for organ damages, the presence or absence of aortic regurgitation (AR), hypertension, ischemic heart disease, cerebrovascular event, visual loss, end-stage renal failure, and inflammatory bowel disease were evaluated. Treatment profiles including immunosuppressive drugs and vascular interventions were also reviewed.Results:The incidence of AR was positively associated with the risk allele of IL12B rs6871626 (p=0.0052; odds ratio (OR) 2.45, 95% confidence interval (CI) 1.27-4.73), and so was the proportion of patients who underwent aortic valve replacement (p=0.023; OR 3.64, 95% CI 1.08-12.24) (table 1). The incidence of hypertension was associated with the risk allele of IL12B rs6871626 (p=0.049; OR 1.82, 95% CI 0.99-3.36) and PTK2B rs2322599 (p=0.044; OR 2.52, 95% CI 0.97-6.54) (table 1). The proportion of biologic users tended to be higher in the risk genotypes of IL12B rs6871626 (p=0.15; OR1.80, 95% CI 0.79-3.99). Regarding vascular damage, there was positive correlation between TADS and the risk allele of IL12B rs6871626 (p=0.0035; β= 1.35) (Figure 1). Moreover, VDI was also positively correlated with the allele (p=0.0054; β= 0.96) (Figure 1). No other clinicogenetic associations were observed between five SNPs and vasculitis-associated damages.Table 1.The association of the five SNPs with aortic regurgitation and hypertensionAortic regurgitationHypertensionOR (95% CI)p valueOR (95% CI)p valueIL12B rs68716262.45 (1.27-4.73)0.0052*1.82 (0.99-3.36)0.049*PTK2B rs23225991.21 (0.51-2.86)0.672.51 (0.97-6.54)0.044*LILRA3 rs1032941.16 (0.52-2.61)0.711.20 (0.55-1.64)0.64DUSP22 rs171336980.56 (0.28-1.13)0.0900.87 (0.46-1.63)0.66KLHL33 rs17134500.89 (0.42-1.91)0.771.48 (0.68-3.22)0.31SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence intervalConclusion:In the present study, IL12B rs6871626 was closely correlated with vascular damage. We also found association between PTK2B rs2322599 and hypertension. There was no significant relevance between vascular damage and LILRA3 rs103294, DUSP22 rs17133698, or KLHL33 rs1713450.References:[1]Terao C et al. Am J Hum Genet. 2013;93(2):289-97.[2]Terao C et al. Proc Natl Acad Sci U S A. 2018;115(51):13045-50.Disclosure of Interests:Keiichiro Kadoba: None declared, Ryu Watanabe Speakers bureau: I have received speaker’s fee from Mitsubishi Tanabe Pharma, Pfizer, Sanofi, AbbVie, Asahi Kasei, Eisai, Eli Lilly, Bristol-Myers Squibb, and Janssen., Takeshi Iwasaki: None declared, Koji Kitagori Grant/research support from: KK has received research grants from GlaxoSmithKline., Syuji Akizuki: None declared, Kosaku Murakami Speakers bureau: I have received speaking fees from Eisai Co. Ltd, Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Corporation, UCB Japan Co. Ltd, Daiichi Sankyo Co. Ltd. and Astellas Pharma Inc., Ran Nakashima: None declared, Motomu Hashimoto Speakers bureau: I have received a research grant and/or speaker fee from Bristol-Myers, Eisai, Ely Lilly, Mitsubishi Tanabe Pharma., Grant/research support from: I have received a research grant and/or speaker fee from Bristol-Myers, Eisai, Ely Lilly, Mitsubishi Tanabe Pharma., Masao Tanaka Speakers bureau: I have received research grants and/or speaker fees from AbbVie GK, Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly and Company, Pfizer Inc., UCB Japan Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Taisho Pharma Co., Ltd, and Takeda Pharmaceutical Company Limited., Koichiro Ohmura Speakers bureau: I have received speaker’s fee from Abbvie, Actelion, Asahikasei Pharma, Astellas, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Janssen, JB, Mitsubishi Tanabe, Nippon Kayaku, Nippon Shinyaku, Novartis, Sanofi and Takeda., Grant/research support from: I have received research grants from GlaxoSmithKline., Akio Morinobu Speakers bureau: I have received speaking fees from Chugai Pharmaceutical Co. Ltd., Grant/research support from: I have received research grants from Chugai Pharmaceutical Co. Ltd., Chikashi Terao: None declared, Hajime Yoshifuji Speakers bureau: I have received lecture fees from Chugai., Consultant of: I have been an advisory board for a clinical trial conducted by Janssen.
16
Stumpf, Anita N., Edith D. van der Meijden, Cornelis A. M. van Bergen, Roelof Willemze, J. H. Frederik Falkenburg, and Marieke Griffioen. "Identification of Four New HLA Class II Restricted Minor Histocompatibility Antigens Contributing to Graft Versus Leukemia Reactivity." Blood 112, no. 11 (November 16, 2008): 3247. http://dx.doi.org/10.1182/blood.v112.11.3247.3247.
Abstract:
Abstract Patients with relapsed hematological malignancies after HLA-matched hematopoietic stem cell transplantation (HSCT) can be effectively treated with donor lymphocyte infusion (DLI). Donor-derived T cells mediate beneficial graft-versus-leukemia (GvL) effect but may also induce detrimental graft-versus-host disease (GvHD). These T cell responses are directed against polymorphic peptides which differ between patient and donor due to single nucleotide polymorphisms (SNPs). These so called minor histocompatibility antigens (mHag) are presented by HLA class I or II, thereby activating CD8+ and CD4+ T cells, respectively. Although a broad range of different HLA class I restricted mHags have been identified, we only recently characterized the first autosomal HLA class II restricted mHag phosphatidylinositol 4-kinase type 2 beta (LB-PI4K2B-1S; PNAS, 2008, 105 (10), p.3837). As HLA class II is predominantly expressed on hematopoietic cells, CD4+ T cells may selectively confer GvL effect without GvHD. Here, we present the molecular identification of four new autosomal HLA class II restricted mHags recognized by CD4+ T cells induced in a patient with relapsed chronic myeloid leukemia (CML) after HLAmatched HSCT who experienced long-term complete remission after DLI with only mild GvHD of the skin. By sorting activated CD4+ T cells from bone marrow mononuclear cells obtained 5 weeks after DLI, 17 highly reactive mHag specific CD4+ T cell clones were isolated. Nine of these T cell clones recognized the previously described HLADQ restricted mHag LB-PI4K2B-1S. The eight remaining T cell clones were shown to exhibit five different new specificities. To determine the recognized T cell epitopes, we used our recently described recombinant bacteria cDNA library. This method proved to be extremely efficient, since four out of five different specificities could be identified as new HLA-class II restricted autosomal mHags. The newly identified mHags were restricted by different HLA-DR molecules of the patient. Two mHags were restricted by HLA-DRB1 and were found to be encoded by the methylene-tetrahydrofolate dehydrogenase 1 (LBMTHFD1- 1Q; DRB1*0301) and lymphocyte antigen 75 (LB-LY75-1K; DRB1*1301) genes. An HLA-DRB3*0101 restricted mHag was identified as LB-PTK2B-1T, which is encoded by the protein tyrosine kinase 2 beta gene. The fourth mHag LB-MR1-1R was restricted by HLA-DRB3*0202 and encoded by the major histocompatibility complex, class I related gene. All newly identified HLA class II restricted mHags exhibit high population frequencies of 25% (LB-MR1-1R), 33% (LB-LY75-1K), 68% (LB-MTHFD1- 1Q), and 70% (LB-PTK2B-1T) and the genes encoding these mHags show selective (LY- 75) or predominant (MR1, MTHFD1, PTK2B) expression in cells of hematopoietic origin as determined by public microarray databases. All T cell clones directed against the newly identified mHags recognized high HLA class II-expressing B-cells, mature dendritic cells (DC) and in vitro cultured leukemic cells with antigen-presenting phenotype. The clone recognizing LB-MTHFD1-1Q also showed direct recognition of CD34+ CML precursor cells from the patient. In conclusion, we molecularly characterized the specificity of the CD4+ T cell response in a patient with CML after HLA-matched HSCT who went into long-term complete remission after DLI. By screening a recombinant bacteria cDNA library, four new different CD4+ T cell specificities were characterized. Our screening method and results open the possibility to identify the role of CD4+ T cells in human GvL and GvHD, and to explore the use of hematopoiesis- and HLA class II-restricted mHag specific T cells in the treatment of hematological malignancies.
17
Allert, C., S. Zimmermann, S. Göllner, D. Heid, M. Bruckmann, M. Janssen, B. Besenbeck, J. Krijgsveld, C. Müller-Tidow, and M. F. Blank. "P382: PTK2B MEDIATES TYROSINE KINASE INHIBITOR DRUG RESISTANCE IN AML ASSOCIATED WITH ALTERED MIGRATION AND ADHESION PROPERTIES." HemaSphere 6 (June 2022): 282–83. http://dx.doi.org/10.1097/01.hs9.0000844416.17053.2a.
18
Beck, Tim N., Emmanuelle Nicolas, Meghan C. Kopp, and Erica A. Golemis. "Adaptors for disorders of the brain? The cancer signaling proteins NEDD9, CASS4, and PTK2B in Alzheimer’s disease." Oncoscience 1, no. 7 (July 12, 2014): 486–503. http://dx.doi.org/10.18632/oncoscience.64.
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Li, Ya-Qing, Meng-Shan Tan, Hui-Fu Wang, Chen-Chen Tan, Wei Zhang, Zhan-Jie Zheng, Ling-Li Kong, et al. "Common variant in PTK2B is associated with late-onset Alzheimer’s disease: A replication study and meta-analyses." Neuroscience Letters 621 (May 2016): 83–87. http://dx.doi.org/10.1016/j.neulet.2016.04.020.
20
Wang, Di, Yunkai Lin, Feihong Xu, Hui Zhang, Xiaoyan Zhu, Zhen Liu, Yuan Hu, et al. "SIRPα maintains macrophage homeostasis by interacting with PTK2B kinase in Mycobacterium tuberculosis infection and through autophagy and necroptosis." eBioMedicine 85 (November 2022): 104278. http://dx.doi.org/10.1016/j.ebiom.2022.104278.
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Dourlen, P., F. J. Fernandez-Gomez, C. Dupont, B. Grenier-Boley, C. Bellenguez, H. Obriot, R. Caillierez, et al. "Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology." Molecular Psychiatry 22, no. 6 (April 26, 2016): 874–83. http://dx.doi.org/10.1038/mp.2016.59.
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Zhang, Lei, Rongrong Luo, Lin Wang, Jiarui Yao, Di Wu, Zhishang Zhang, Xiaohong Han, and Yuankai Shi. "Prediction of EGFR-TKI efficacy in non-small cell lung cancer patients by metabolomics and genomics." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e20627-e20627. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e20627.
Abstract:
e20627 Background: Metabolites and somatic mutations involved in EGFR-TKI efficacy remains unclear in non-small cell lung cancer (NSCLC) patients with EGFR sensitizing mutation (EGFRsm+). Here we performed a joint analysis of metabolomics and genomics data to identify metabolites and somatic mutations as biomarkers for EGFR-TKI efficacy. Methods: Metabolomic profiling of plasma samples (n = 43) from NSCLC patients with EGFRsm+, consisting of cohort A (n = 30) and B (n = 13), was conducted using UPLC or rapid separation LC-MS/MS. The 13 matched FFPE samples in cohort B were also used in the targeted sequencing below. FFPE samples (n = 18) from NSCLC patients with EGFRsm+ were subjected to targeted sequencing. According to progression free survival (PFS), all patients were assigned a status of poor (PFS≤42 weeks) and good responders (PFS > 42 weeks). A joint analysis of metabolomics and genomics data was adopted to identify biomarkers for EGFR-TKI efficacy. Results: The partial least squares discrimination analysis mothod was performed to establish a prediction model responsible for separation of good and poor responders in cohort A, comprising 27 metabolites with variable importance in projection score (VIP) > 1.5. Based on the prediction model, the ROC analysis demonstrated the sensitivity of 0.8, the specificity of 0.75, and the area under the ROC curve (AUC) of 0.7 in cohort B. The Welch’s t test method identified 15 significant metabolites ( P < 0.05) in cohort A. With the criteria of VIP > 1.5 and P < 0.05, four metabolites, 3-Methyl-L-Histidine, LysoPE(18:2(9Z,12Z)/0:0), Histamine, and SM(d18:1/16:0), were detected as potential biomarkers. To further validate them, associations of these metabolites and somatic mutations were explored in 13 patients with both metabolomics and genomics data available using the Welch’s t test. The results revealed patients with either CTCF R415X or PTK2B G491X had significantly lower Histamine level compared with those without either mutation (both P < 0.05), and significantly increased level of SM(d18:1/16:0) was observed in patients with either GATA2 P250A or MAGI1 S763X (both P < 0.05). Intriguingly, worse PFS was showed in patients with any mutation of GATA2 P250A ( P = 0.02), CTCF R415X ( P = 0.002), PTK2B G491X ( P = 0.002), and MAGI1 S763X ( P = 0.0007). Conclusions: Our joint analysis identified two plasma metabolites and four somatic mutations as biomarkers for EGFR-TKI efficacy. The present findings may provide insights into molecular mechanisms of EGFR-TKI efficacy. Further validation in prospective studies was warranted.
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Bianchini, Laurence, Georges Maire, Bernard Guillot, Jean-Marie Joujoux, Philippe Follana, Marie-Pierre Simon, Jean-Michel Coindre, and Florence Pedeutour. "Complex t(5;8) involving the CSPG2 and PTK2B genes in a case of dermatofibrosarcoma protuberans without the COL1A1-PDGFB fusion." Virchows Archiv 452, no. 6 (February 6, 2008): 689–96. http://dx.doi.org/10.1007/s00428-008-0580-2.
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Astillero-Lopez, Veronica, Sandra Villar-Conde, Melania Gonzalez-Rodriguez, Alicia Flores-Cuadrado, Isabel Ubeda-Banon, Daniel Saiz-Sanchez, and Alino Martinez-Marcos. "ROLE OF ANXA2, HSP90AA1 AND PTK2B IN SYNAPTIC HOMEOSTASIS THROUGH MICROGLIAL CELLS IN THE HUMAN ENTORHINAL CORTEX IN ALZHEIMER’S DISEASE." IBRO Neuroscience Reports 15 (October 2023): S361. http://dx.doi.org/10.1016/j.ibneur.2023.08.680.
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Xu, Chao, Jing Shi, Rufeng Huang, Zhengchang Wu, Shenglong Wu, and Wenbin Bao. "Transcriptome-Wide lncRNA and mRNA Profiling of Spleens from Meishan Pigs at Different Development Stages." Animals 12, no. 19 (October 5, 2022): 2676. http://dx.doi.org/10.3390/ani12192676.
Abstract:
Meishan is a well-established local Chinese breed known for its high fecundity, strong immune response and high meat quality. However, the molecular mechanism of immune regulation during the development of Meishan pigs still remains unclear. Here, we performed the transcriptional sequencing of spleen tissues from Meishan pigs at different development stages. In total, 10,268 lncRNAs were identified, including 1254 novel lncRNAs and 9014 known lncRNAs. Time series analysis revealed that genes of the up-regulated module were enriched in pathways associated with transport, immunity, and histone acetylation modifications, while genes of the down-regulated module were enriched in DNA metabolic process and cell cycle. Weighted gene co-expression network analysis (WGCNA) showed the functional linkage between mRNAs and lncRNAs, indicating that lncRNAs are important regulatory elements of mRNAs. Notably, a lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network that contained 3 mRNAs (AKT3, CBL and PTK2B), 17 lncRNAs and 67 miRNAs were screened out, which probably plays a critical role in immune regulation of Meishan pigs. Our findings not only revealed the transcriptome profile of spleen development, but also provide novel insights into the mechanism of lncRNA-miRNA-mRNA axis in the immune response in Meishan pigs.
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Batissoco, Ana, Rodrigo Salazar-Silva, Jeanne Oiticica, Ricardo Bento, Regina Mingroni-Netto, and Luciana Haddad. "A Cell Junctional Protein Network Associated with Connexin-26." International Journal of Molecular Sciences 19, no. 9 (August 27, 2018): 2535. http://dx.doi.org/10.3390/ijms19092535.
Abstract:
GJB2 mutations are the leading cause of non-syndromic inherited hearing loss. GJB2 encodes connexin-26 (CX26), which is a connexin (CX) family protein expressed in cochlea, skin, liver, and brain, displaying short cytoplasmic N-termini and C-termini. We searched for CX26 C-terminus binding partners by affinity capture and identified 12 unique proteins associated with cell junctions or cytoskeleton (CGN, DAAM1, FLNB, GAPDH, HOMER2, MAP7, MAPRE2 (EB2), JUP, PTK2B, RAI14, TJP1, and VCL) by using mass spectrometry. We show that, similar to other CX family members, CX26 co-fractionates with TJP1, VCL, and EB2 (EB1 paralogue) as well as the membrane-associated protein ASS1. The adaptor protein CGN (cingulin) co-immuno-precipitates with CX26, ASS1, and TJP1. In addition, CGN co-immunoprecipitation with CX30, CX31, and CX43 indicates that CX association is independent on the CX C-terminus length or sequence. CX26, CGN, FLNB, and DAMM1 were shown to distribute to the organ of Corti and hepatocyte plasma membrane. In the mouse liver, CX26 and TJP1 co-localized at the plasma membrane. In conclusion, CX26 associates with components of other membrane junctions that integrate with the cytoskeleton.
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Tasian, Sarah K., Mignon L. Loh, and Stephen P. Hunger. "Philadelphia chromosome–like acute lymphoblastic leukemia." Blood 130, no. 19 (November 9, 2017): 2064–72. http://dx.doi.org/10.1182/blood-2017-06-743252.
Abstract:
AbstractPhiladelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), also referred to as BCR-ABL1–like ALL, is a high-risk subset with a gene expression profile that shares significant overlap with that of Ph-positive (Ph+) ALL and is suggestive of activated kinase signaling. Although Ph+ ALL is defined by BCR-ABL1 fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1 and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling. Additional genomic alterations in Ph-like ALL activate other kinases, including BLNK, DGKH, FGFR1, IL2RB, LYN, NTRK3, PDGFRA, PTK2B, TYK2, and the RAS signaling pathway. Recent studies have helped to define the genomic landscape of Ph-like ALL and how it varies across the age spectrum, associated clinical features and outcomes, and genetic risk factors. Preclinical studies and anecdotal reports show that targeted inhibitors of relevant signaling pathways are active in specific Ph-like ALL subsets, and precision medicine trials have been initiated for this high-risk ALL subset.
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Padhy, Biswajit, Bushra Hayat, Gargi Gouranga Nanda, Pranjya Paramita Mohanty, and Debasmita Pankaj Alone. "Pseudoexfoliation and Alzheimer's associated CLU risk variant, rs2279590 lies within an enhancer element and regulates CLU, EPHX2 and PTK2B gene expression." Canadian Journal of Biotechnology 1, Special Issue (October 5, 2017): 90. http://dx.doi.org/10.24870/cjb.2017-a77.
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Kremer, A. N., J. C. van der Griendt, E. D. van der Meijden, M. W. Honders, B. Ayoglu, J. M. Schwenk, P. Nilsson, J. H. F. Falkenburg, and M. Griffioen. "Development of a coordinated allo T cell and auto B cell response against autosomal PTK2B after allogeneic hematopoietic stem cell transplantation." Haematologica 99, no. 2 (October 4, 2013): 365–69. http://dx.doi.org/10.3324/haematol.2013.086652.
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Padhy, Biswajit, Bushra Hayat, Gargi Gouranga Nanda, Pranjya Paramita Mohanty, and Debasmita Pankaj Alone. "Pseudoexfoliation and Alzheimer’s associated CLU risk variant, rs2279590, lies within an enhancer element and regulates CLU, EPHX2 and PTK2B gene expression." Human Molecular Genetics 26, no. 22 (August 26, 2017): 4519–29. http://dx.doi.org/10.1093/hmg/ddx329.
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Racioppi, Luigi, Pamela Noeldner, Fumin Lin, Stephanie Arvai, and Anthony Means. "Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 Regulates Macrophage-Mediated Inflammatory Responses (172.35)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 172.35. http://dx.doi.org/10.4049/jimmunol.188.supp.172.35.
Abstract:
Abstract Calcium/calmodulin-dependent Kinase Kinase 2 (CaMKK2) plays a key role in regulating food intake and energy expenditure at least in part by its actions in hypothalamic neurons. Previously we showed that loss of CaMKK2 protected mice from high fat diet (HFD)-induced obesity and glucose intolerance. However, whereas pair-feeding HFD to WT mice to match food consumption of CAMKK2-null mice slowed weight gain, it failed to protect from glucose intolerance. Here we show that relative to WT mice, HFD-fed CaMKK2-null mice are protected from inflammation in adipose and remain glucose tolerant. Moreover, loss of CaMKK2 also protected mice from endotoxin shock and fulminant hepatitis. We explored the expression of CaMKK2 in immune cells, and found it to be restricted to those of the monocyte/macrophage lineage. CaMKK2-null macrophages exhibited a remarkable deficiency to spread, phagocytize bacteria and synthesize cytokines in response to the Toll Like Receptor 4 (TLR4) agonist lipopolysaccharide (LPS). Mechanistically, loss of CaMKK2 uncoupled the TLR4 cascade from activation of protein tyrosine kinase 2 (PYK2; also known as PTK2B). Our findings uncover an important function for CaMKK2 in mediating mechanisms that control the amplitude of macrophage inflammatory responses to excess nutrients or pathogen derivatives.
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Prell, Andreas, Mustafa Orkun Sen, Ramya Potabattula, Laura Bernhardt, Marcus Dittrich, Thomas Hahn, Martin Schorsch, et al. "Species-Specific Paternal Age Effects and Sperm Methylation Levels of Developmentally Important Genes." Cells 11, no. 4 (February 19, 2022): 731. http://dx.doi.org/10.3390/cells11040731.
Abstract:
A growing number of sperm methylome analyses have identified genomic loci that are susceptible to paternal age effects in a variety of mammalian species, including human, bovine, and mouse. However, there is little overlap between different data sets. Here, we studied whether or not paternal age effects on the sperm epigenome have been conserved in mammalian evolution and compared methylation patterns of orthologous regulatory regions (mainly gene promoters) containing both conserved and non-conserved CpG sites in 94 human, 36 bovine, and 94 mouse sperm samples, using bisulfite pyrosequencing. We discovered three (NFKB2, RASGEF1C, and RPL6) age-related differentially methylated regions (ageDMRs) in humans, four (CHD7, HDAC11, PAK1, and PTK2B) in bovines, and three (Def6, Nrxn2, and Tbx19) in mice. Remarkably, the identified sperm ageDMRs were all species-specific. Most ageDMRs were in genomic regions with medium methylation levels and large methylation variation. Orthologous regions in species not showing this age effect were either hypermethylated (>80%) or hypomethylated (<20%). In humans and mice, ageDMRs lost methylation, whereas bovine ageDMRs gained methylation with age. Our results are in line with the hypothesis that sperm ageDMRs are in regions under epigenomic evolution and may be part of an epigenetic mechanism(s) for lineage-specific environmental adaptations and provide a solid basis for studies on downstream effects in the genes analyzed here.
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Haas, Laura T., and Stephen M. Strittmatter. "Oligomers of Amyloid β Prevent Physiological Activation of the Cellular Prion Protein-Metabotropic Glutamate Receptor 5 Complex by Glutamate in Alzheimer Disease." Journal of Biological Chemistry 291, no. 33 (June 20, 2016): 17112–21. http://dx.doi.org/10.1074/jbc.m116.720664.
Abstract:
The dysfunction and loss of synapses in Alzheimer disease are central to dementia symptoms. We have recently demonstrated that pathological Amyloid β oligomer (Aβo) regulates the association between intracellular protein mediators and the synaptic receptor complex composed of cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5). Here we sought to determine whether Aβo alters the physiological signaling of the PrPC-mGluR5 complex upon glutamate activation. We provide evidence that acute exposure to Aβo as well as chronic expression of familial Alzheimer disease mutant transgenes in model mice prevents protein-protein interaction changes of the complex induced by the glutamate analog 3,5-dihydroxyphenylglycine. We further show that 3,5-dihydroxyphenylglycine triggers the phosphorylation and activation of protein-tyrosine kinase 2-β (PTK2B, also referred to as Pyk2) and of calcium/calmodulin-dependent protein kinase II in wild-type brain slices but not in Alzheimer disease transgenic brain slices or wild-type slices incubated with Aβo. This study further distinguishes two separate Aβo-dependent signaling cascades, one dependent on extracellular Ca2+ and Fyn kinase activation and the other dependent on the release of Ca2+ from intracellular stores. Thus, Aβo triggers multiple distinct PrPC-mGluR5-dependent events implicated in neurodegeneration and dementia. We propose that targeting the PrPC-mGluR5 complex will reverse aberrant Aβo-triggered states of the complex to allow physiological fluctuations of glutamate signaling.
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Thorne, Jacob W., Reid Redden, Scott A. Bowdridge, Gabrielle M. Becker, Morgan R. Stegemiller, and Brenda M. Murdoch. "Genome-Wide Analysis of Sheep Artificially or Naturally Infected with Gastrointestinal Nematodes." Genes 14, no. 7 (June 26, 2023): 1342. http://dx.doi.org/10.3390/genes14071342.
Abstract:
The anthelmintic resistance of gastrointestinal nematodes (GINs) poses a significant threat to sheep worldwide, but genomic selection can serve as an alternative to the use of chemical treatment as a solution for parasitic infection. The objective of this study is to conduct genome-wide association studies (GWASs) to identify single nucleotide polymorphisms (SNPs) in Rambouillet (RA) and Dorper × White Dorper (DWD) lambs associated with the biological response to a GIN infection. All lambs were genotyped with a medium-density genomic panel with 40,598 markers used for analysis. Separate GWASs were conducted using fecal egg counts (FECs) from lambs (<1 year of age) that acquired their artificial infections via an oral inoculation of 10,000 Haemonchus contortus larvae (n = 145) or naturally while grazing on pasture (n = 184). A GWAS was also performed for packed cell volume (PCV) in artificially GIN-challenged lambs. A total of 26 SNPs exceeded significance and 21 SNPs were in or within 20 kb of genes such as SCUBE1, GALNT6, IGF1R, CAPZB and PTK2B. The ontology analysis of candidate genes signifies the importance of immune cell development, mucin production and cellular signaling for coagulation and wound healing following epithelial damage in the abomasal gastric pits via H. contortus during GIN infection in lambs. These results add to a growing body of the literature that promotes the use of genomic selection for increased sheep resistance to GINs.
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Beverdam, Annemiek, Terje Svingen, Stefan Bagheri-Fam, Peter McClive, Andrew H. Sinclair, Vincent R. Harley, and Peter Koopman. "Protein tyrosine kinase 2 beta (PTK2B), but not focal adhesion kinase (FAK), is expressed in a sexually dimorphic pattern in developing mouse gonads." Developmental Dynamics 239, no. 10 (August 24, 2010): 2735–41. http://dx.doi.org/10.1002/dvdy.22396.
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Crews, Leslie A., Larissa Balaian, Heather Leu, Nathaniel Delos Santos, Angela C. Court, Anil Sadarangani, Maria A. Zipeto, et al. "RNA Splicing Modulation Impairs Acute Myeloid Leukemia Stem Cell Maintenance." Blood 126, no. 23 (December 3, 2015): 567. http://dx.doi.org/10.1182/blood.v126.23.567.567.
Abstract:
Abstract Introduction Disease relapse is the leading cause of death in secondary AML (sAML), which evolves from antecedent hematologic disorders like myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPNs) or following exposure to chemotherapy. Persistence of therapy-resistant leukemia stem cells (LSC) harboring enhanced survival and self-renewal capacity has been linked to high relapse rates in sAML. Previously, we showed that missplicing of a stem cell regulatory gene, GSK3 b, and splice isoform switching favoring pro-survival BCL2 family isoform expression promoted generation of therapy-resistant LSC (Abrahamsson et al PNAS 2009; Goff et al Cell Stem Cell 2013). However, whether aberrant pre-mRNA splicing promotes sAML LSC generation, in the absence of mutation, and if pharmacological splicing modulation impairs LSC maintenance, in a mutation-independent manner, has not been elucidated. Methods and Results Comparative RNA-sequencing and gene set enrichment analyses revealed significant alterations in splicing factor gene expression in purified progenitors from untreated sAML compared with normal samples. In addition, using an isoform-specific alignment algorithm, we established a sAML LSC splice isoform expression signature that identified increased expression of select transcripts, e.g. CD82 and PTK2B. Thus, we investigated the LSC inhibitory efficacy of a stable, potent splicing modulatory agent, 17S -FD-895, in humanized AML LSC stromal co-culture and primagraft assays. Notably, there was a dose-dependent reduction in AML LSC (n=4) survival and self-renewal after in vitro 17S -FD-895 treatment, with a favorable therapeutic index compared to normal controls (n=3, p<0.01). Splicing reporter activity and PCR analyses revealed rapid and potent 17S -FD-895-induced alterations in splicing, promoting pro-apoptotic isoform expression and intron inclusion in the stem cell regulatory gene MCL1. Also, 17S -FD-895 restored normal expression patterns of PTK2B, and MCL1-L/S and BLC2-L/S expression ratios. Flow cytometric analyses in AML LSC primagraft models treated with 17S -FD-895 (5-10 mg/kg delivered intravenously in 3 doses over 2 weeks) revealed a decrease in human stem (CD45+ CD34+ CD38- Lin-, 68% reduction in the spleens of the 10 mg/kg group versus vehicle controls, n=5 mice per group, p<0.05) and progenitor (CD45+ CD34+ CD38+ Lin-, 80% reduction to nearly zero in the spleens of the 10 mg/kg group versus vehicle controls, p=0.08) cell frequencies. Furthermore, MCL1-L/S and BCL2-L/S expression ratios were significantly reduced in LSC-enriched fractions from 17S -FD-895-treated mice compared to vehicle controls. Consistent with a reduction in functional LSC burden after 17S -FD-895 treatment, subsequent serial transplantation studies showed a 47-65% reduction in leukemic burden in the hematopoietic tissues of recipients of CD34+ cells from mice in the 10 mg/kg treatment group versus vehicle controls (n=5 mice per group, p<0.05). Conclusions Here we demonstrate that a potent and stable splicing modulatory agent, 17S -FD-895, normalized sAML-specific splice isoform expression patterns as well as MCL1-L/S and BLC2-L/S ratios. Moreover, pharmacologic splicing modulation reduced AML LSC survival and self-renewal in a dose-dependent manner in both in vitro and in vivo models with a favorable therapeutic index. Further evaluation of this compound as a splicing-targeted single agent or combined with standard of care therapy may reduce or eradicate LSC burden in therapy-resistant sAML. In addition, LSC-specific splice isoforms may represent important biomarkers that could be developed as companion diagnostics for splicing-targeted therapies in sAML and other recalcitrant malignancies. Disclosures Jamieson: Johnson & Johnson: Research Funding; GlaxoSmithKline: Research Funding.
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Schmitt, Anthony, Shadi Melnyk, Kristin Sikkink, Lisa Lansdon, Tomi Pastinen, Erin Guest, and Midhat Farooqi. "Abstract LB122: Arima-HiC sequencing accurately detects clinically-relevant structural variants in pediatric leukemia samples." Cancer Research 83, no. 8_Supplement (April 14, 2023): LB122. http://dx.doi.org/10.1158/1538-7445.am2023-lb122.
Abstract:
Abstract Genetic structural variants (SVs), especially those leading to gene fusions, are well-known oncogenic drivers. These SVs can produce overexpression or loss-of-function of certain genes, or generate chimeric fusion proteins. Thus, they serve as important disease biomarkers across several cancers and can also represent therapeutically targetable alterations. Detecting these SVs at a gene-level resolution can be challenging with lower resolution karyotyping approaches, or even RNA sequencing approaches, due to difficulties with culture, sample stability, low transcript abundance, or low-quality RNA. In addition, the ability of fluorescence in situ hybridization (FISH) techniques to detect gene fusions is limited by the targeted nature of these assays as they depend heavily on the design and selection of each probe. Here we use a novel method, Arima-HiC sequencing, that utilizes DNA to evaluate 12 pediatric leukemia samples and determine this assay’s effectiveness in detecting clinically-relevant SVs. We first selected 5 archived (cryopreserved) pediatric acute myeloid leukemia (AML) samples (archival period range: 1-4 years) known to be either fusion-positive (n=3) or fusion-negative (n=2) via prior clinical genetic testing (i.e., chromosomes, FISH, and/or microarray). All samples underwent Arima-HiC sequencing. Briefly, chromatin digestion, end-labeling, and proximity ligation were performed prior to DNA purification per the Arima-HiC protocol. Purified DNA was next prepared as a short-read sequencing library and sequenced on a HiSeq X. The raw reads were aligned and deduplicated, and SVs were called using HiC-Breakfinder software. For a discovery set, we then additionally selected 7 pediatric leukemia samples—6 precursor B-cell acute lymphoblastic leukemias (ALL) and 1 AML—for Arima-HiC sequencing (as above). These cases had undergone standard-of-care cytogenetic (karyotyping, FISH, microarray) and/or molecular (targeted cancer NGS sequencing panel) testing clinically, and a genetic driver/known gene fusion had not been identified. Using Arima-HiC sequencing, we identified the clinically-relevant SV in each of our 3 fusion-positive AML cases, consistent with the original diagnostic cytogenetic finding (n= 1 RUNX1-RUNX1T1 fusion, 1 CBFB-MYH11 fusion, and 1 CBFA2T3-GLIS2 fusion). The 2 fusion-negative AML cases were also negative for structural gene fusions by HiC data. In our discovery sample set, Arima-HiC sequencing was able to find clinically-relevant SVs that were not previously detected in 3 of 6 samples: a KMT2A-MLLT10 fusion was found in an AML case, and a ZNF384-EP300 fusion was found in each of 2 ALL cases. A ABHD17B-PTK2B fusion was found in another ALL case, although ABHD17B may be a novel partner PTK2B and is undergoing validation. Rearrangements involving KRAS and EGFR were detected in the final two ALL cases, and are also undergoing validation. Overall, this study demonstrates how Arima-HiC sequencing can provide diagnostic value in pediatric leukemia specimens via the identification of clinically relevant SVs. Citation Format: Anthony Schmitt, Shadi Melnyk, Kristin Sikkink, Lisa Lansdon, Tomi Pastinen, Erin Guest, Midhat Farooqi. Arima-HiC sequencing accurately detects clinically-relevant structural variants in pediatric leukemia samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB122.
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Li, Ya-Qing, Meng-Shan Tan, Hui-Fu Wang, Chen-Chen Tan, Wei Zhang, Zhan-Jie Zheng, Ling-Li Kong, et al. "Corrigendum to “Common variant in PTK2B is associated with late-onset Alzheimer’s disease: A replication study and meta-analyses” [Neurosci. Lett. 621 (2016) 83–87]." Neuroscience Letters 626 (July 2016): 182. http://dx.doi.org/10.1016/j.neulet.2016.05.023.
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Li, Xingming, Yuliang Cheng, Jiayi Li, Chang Liu, He Qian, and Genyi Zhang. "Torularhodin Alleviates Hepatic Dyslipidemia and Inflammations in High-Fat Diet-Induced Obese Mice via PPARα Signaling Pathway." Molecules 27, no. 19 (September 27, 2022): 6398. http://dx.doi.org/10.3390/molecules27196398.
Abstract:
Torularhodin is a β-carotene-like compound from Sporidiobolus pararoseus, and its protective effect against high-fat diet (HFD)-induced hepatic dyslipidemia and inflammation was investigated. Compared to mice of C57BL/6J fed on HFD, the addition of Torularhodin into the HFD (HFD-T) significantly reduced body weight, serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), and the inflammatory mediators of TNF-α, IL-6, IL-1β, and lipopolysaccharide (LPS). A significant increase of high-density lipoprotein cholesterol (HDL-c), which is beneficial to cholesterol clearance, was also observed in HFD-T group. Proteomic analysis showed HDL-C-c is highly correlated with proteins (e.g., CPT1A and CYP7A1) involved in lipid β-oxidation and bile acid synthesis, whereas the other phenotypic parameters (TC, TG, LDL, and inflammatory cytokines) are highly associated with proteins (e.g., SLC27A4) involved in lipid-uptake. The up-regulated anti-inflammation proteins FAS, BAX, ICAM1, OCLN, GSTP1, FAF1, LRP1, APEX1, ROCK1, MANF, STAT3, and INSR and down-regulated pro-inflammatory proteins OPTN, PTK2B, FADD, MIF, CASP3, YAP1, DNM1L, and NAMPT not only demonstrate the occurrence of HFD-induced hepatic inflammation, but also prove the anti-inflammatory property of Torularhodin. KEGG signaling pathway analysis revealed that the PPARα signaling pathway is likely fundamental to the health function of Torularhodin through up-regulating genes related to fatty acid β-oxidation, cholesterol excretion, HDL-Cc formation, and anti-inflammation. Torularhodin, as a new food resource, may act as a therapeutic agent to prevent hepatic dyslipidemia and related inflammation for improved health.
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Detroja, Trishna Saha, Hava Gil-Henn, and Abraham O. Samson. "Text-Mining Approach to Identify Hub Genes of Cancer Metastasis and Potential Drug Repurposing to Target Them." Journal of Clinical Medicine 11, no. 8 (April 11, 2022): 2130. http://dx.doi.org/10.3390/jcm11082130.
Abstract:
Metastasis accounts for the majority of cancer-related deaths. Despite decades of research, the prevention and suppression of metastasis remain an elusive goal, and to date, only a few metastasis-related genes have been targeted therapeutically. Thus, there is a strong need to find potential genes involved in key driver traits of metastasis and their available drugs. In this study, we identified genes associated with metastasis and repurposable drugs that potentially target them. First, we use text mining of PubMed citations to identify candidate genes associated with metastatic processes, such as invadopodia, motility, movement, metastasis, invasion, wound healing, EMT (epithelial to mesenchymal transition), and podosome. Next, we annotated the top genes involved in each process as a driver, tumor suppressor, or oncogene. Then, a total of 185 unique cancer genes involved in metastasis-related processes were used for hub gene analysis using bioinformatics tools. Notably, a total of 77 hub genes were identified. Further, we used virtual screening data of druggable candidate hub genes involved in metastasis and identified potential drugs that can be repurposed as anti-metastatic drugs. Remarkably, we found a total of 50 approved drugs that have the potential to be repurposed against 19 hub genes involved in metastasis-related processes. These 50 drugs were also found to be validated in different cancer cell lines, such as dasatinib, captopril, leflunomide, and dextromethorphan targeting SRC, MMP2, PTK2B, and RAC1 hub genes, respectively. These repurposed drugs potentially target metastasis, provide pharmacodynamic insight, and offer a window of opportunity for the development of much-needed antimetastatic drugs.
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Xu, Qili, Aili Song, and Qigui Xie. "The Integrated Analyses of Driver Genes Identify Key Biomarkers in Thyroid Cancer." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382094044. http://dx.doi.org/10.1177/1533033820940440.
Abstract:
Aim: Thyroid cancer is the most common endocrine cancer, the incidence rate has continuously increased worldwide. However, there are still lack of effective molecular biomarkers for the diagnosis and treatment of the disease. The study was conducted to identify driver genes that may serve as potential biomarkers for the disease. Methods: The computational tools oncodriveCLUST, oncodriveFM, icages and drgap were used to detect driver genes in thyroid cancer using somatic mutations from The Cancer Genome Atlas database. Integrated analyses were performed on the driver genes using multiomics data from the TCGA database. Results: A set of 291 driver genes were identified in thyroid cancer. BRAF, NRAS, HRAS, OTUD4, EIF1AX were the top 5 frequently mutated genes in thyroid cancer. The weighted gene co-expression network analysis identified 4 coexpression modules. The modules 1-3 were significantly associated with patients’ tumor size, residual tumor, cancer stage, distant metastasis and multifocality. SEC24B, MET and ITGAL were the hub genes in the modules 1-3 respectively. Hierarchical clustering analysis of the 20 driver genes with the most frequent copy number changes revealed 3 clusters of PRAD patients. Cluster 1 tumors exhibited significantly older age, tumor size, cancer stages, and poorer prognosis than cluster 2 and 3 tumors. 16 genes were significantly associated with number of lymph nodes, tumor size and pathologic stage, such as IL7 R, IRS1, PTK2B, MAP3K3 and FGFR2. Conclusions: The set of cancer genes and subgroups of patients shed insight on the tumorigenesis of thyroid cancer and open up avenues for developing prognostic biomarkers and driver gene-targeted therapies in thyroid cancer.
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Shah, Manasvi S., Scott L. Schwartz, Chen Zhao, Laurie A. Davidson, Beiyan Zhou, Joanne R. Lupton, Ivan Ivanov, and Robert S. Chapkin. "Integrated microRNA and mRNA expression profiling in a rat colon carcinogenesis model: effect of a chemo-protective diet." Physiological Genomics 43, no. 10 (May 2011): 640–54. http://dx.doi.org/10.1152/physiolgenomics.00213.2010.
Abstract:
We have recently demonstrated that nutritional bioactives (fish oil and pectin) modulate microRNA molecular switches in the colon. Since integrated analysis of microRNA and mRNA expression at an early stage of colon cancer development is lacking, in this study, four computational approaches were utilized to test the hypothesis that microRNAs and their posttranscriptionally regulated mRNA targets, i.e., both total mRNAs and actively translated mRNA transcripts, are differentially modulated by carcinogen and diet treatment. Sprague-Dawley rats were fed diets containing corn oil ± fish oil with pectin ± cellulose and injected with azoxymethane or saline (control). Colonic mucosa was assayed at an early time of cancer progression, and global gene set enrichment analysis was used to obtain those microRNAs significantly enriched by the change in expression of their putative target genes. In addition, cumulative distribution function plots and functional network analyses were used to evaluate the impact of diet and carcinogen combination on mRNA levels induced via microRNA alterations. Finally, linear discriminant analysis was used to identify the best single-, two-, and three-microRNA combinations for classifying dietary effects and colon tumor development. We demonstrate that polysomal profiling is tightly related to microRNA changes when compared with total mRNA profiling. In addition, diet and carcinogen exposure modulated a number of microRNAs (miR-16, miR-19b, miR-21, miR26b, miR27b, miR-93, and miR-203) linked to canonical oncogenic signaling pathways. Complementary gene expression analyses showed that oncogenic PTK2B, PDE4B, and TCF4 were suppressed by the chemoprotective diet at both the mRNA and protein levels.
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Stavchansky, Vasily V., Ivan B. Filippenkov, Julia A. Remizova, Alina E. Denisova, Ivan V. Mozgovoy, Leonid V. Gubsky, Nikolay F. Myasoedov, Lyudmila A. Andreeva, Svetlana A. Limborska, and Lyudmila V. Dergunova. "Insight into Glyproline Peptides’ Activity through the Modulation of the Inflammatory and Neurosignaling Genetic Response Following Cerebral Ischemia–Reperfusion." Genes 13, no. 12 (December 16, 2022): 2380. http://dx.doi.org/10.3390/genes13122380.
Abstract:
Glyprolines are Gly-Pro (GP)- or Pro-Gly (PG)-containing biogenic peptides. These peptides can act as neutrophil chemoattractants, or atheroprotective, anticoagulant, and neuroprotective agents. The Pro-Gly-Pro (PGP) tripeptide is an active factor of resistance to the biodegradation of peptide drugs. The synthetic Semax peptide, which includes Met-Glu-His-Phe (MEHF) fragments of adrenocorticotropic hormone and the C-terminal tripeptide PGP, serves as a neuroprotective drug for the treatment of ischemic stroke. Previously, we revealed that Semax mostly prevented the disruption of the gene expression pattern 24 h after a transient middle cerebral artery occlusion (tMCAO) in a rat brain model. The genes of this pattern were grouped into an inflammatory cluster (IC) and a neurotransmitter cluster (NC). Here, using real-time RT-PCR, the effect of other PGP-containing peptides, PGP and Pro-Gly-Pro-Leu (PGPL), on the expression of a number of genes in the IC and NC was studied 24 h after tMCAO. Both the PGP and PGPL peptides showed Semax-unlike effects, predominantly without changing gene expression 24 h after tMCAO. Moreover, there were IC genes (iL1b, iL6, and Socs3) for PGP, as well as IC (iL6, Ccl3, Socs3, and Fos) and NC genes (Cplx2, Neurod6, and Ptk2b) for PGPL, that significantly changed in expression levels after peptide administration compared to Semax treatment under tMCAO conditions. Furthermore, gene enrichment analysis was carried out, and a regulatory gene network was constructed. Thus, the spectra of the common and unique effects of the PGP, PGPL, and Semax peptides under ischemia–reperfusion were distinguished.
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Tawa, Gregory J., John Braisted, David Gerhold, Gurmit Grewal, Christina Mazcko, Matthew Breen, Gurusingham Sittampalam, and Amy K. LeBlanc. "Transcriptomic profiling in canines and humans reveals cancer specific gene modules and biological mechanisms common to both species." PLOS Computational Biology 17, no. 9 (September 27, 2021): e1009450. http://dx.doi.org/10.1371/journal.pcbi.1009450.
Abstract:
Understanding relationships between spontaneous cancer in companion (pet) canines and humans can facilitate biomarker and drug development in both species. Towards this end we developed an experimental-bioinformatic protocol that analyzes canine transcriptomics data in the context of existing human data to evaluate comparative relevance of canine to human cancer. We used this protocol to characterize five canine cancers: melanoma, osteosarcoma, pulmonary carcinoma, B- and T-cell lymphoma, in 60 dogs. We applied an unsupervised, iterative clustering method that yielded five co-expression modules and found that each cancer exhibited a unique module expression profile. We constructed cancer models based on the co-expression modules and used the models to successfully classify the canine data. These canine-derived models also successfully classified human tumors representing the same cancers, indicating shared cancer biology between canines and humans. Annotation of the module genes identified cancer specific pathways relevant to cells-of-origin and tumor biology. For example, annotations associated with melanin production (PMEL, GPNMB, and BACE2), synthesis of bone material (COL5A2, COL6A3, and COL12A1), synthesis of pulmonary surfactant (CTSH, LPCAT1, and NAPSA), ribosomal proteins (RPL8, RPS7, and RPLP0), and epigenetic regulation (EDEM1, PTK2B, and JAK1) were unique to melanoma, osteosarcoma, pulmonary carcinoma, B- and T-cell lymphoma, respectively. In total, 152 biomarker candidates were selected from highly expressing modules for each cancer type. Many of these biomarker candidates are under-explored as drug discovery targets and warrant further study. The demonstrated transferability of classification models from canines to humans enforces the idea that tumor biology, biomarker targets, and associated therapeutics, discovered in canines, may translate to human medicine.
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Wang, Yan, Zhongyv Xiong, Chang Li, Dong Liu, Xiaogang Li, Junyv Xu, Niangen Chen, Xuesong Wang, Qifu Li, and Youbin Li. "Multiple Beneficial Effects of Aloesone from Aloe vera on LPS-Induced RAW264.7 Cells, Including the Inhibition of Oxidative Stress, Inflammation, M1 Polarization, and Apoptosis." Molecules 28, no. 4 (February 8, 2023): 1617. http://dx.doi.org/10.3390/molecules28041617.
Abstract:
Aloesone is a major metabolic compound in Aloe vera, which has been widely used as a food source and therapeutic agent in several countries. Our recent study demonstrated that aloesone has anti-epileptic effects on glutamate-induced neuronal injury by suppressing the production of reactive oxygen species (ROS). Unless ROS are naturally neutralized by the endogenous antioxidant system, they lead to the activation of inflammation, polarization, and apoptosis. This study aimed to identify the multiple beneficial effects of aloesone and explore its molecular mechanism in macrophages. Hence, the murine macrophage cell line RAW264.7 was pretreated with aloesone and then exposed to lipopolysaccharides (LPS). The results demonstrated that aloesone, within a dosage range of 0.1–100 µM, dramatically decreased the LPS-induced elevation of ROS production, reduced nitric oxide (NO) release, inhibited the M1 polarization of RAW264.7 cells, and prevented cells from entering the LPS-induced early and late phases of apoptosis in a dose-dependent manner. Simultaneously, aloesone significantly decreased the mRNA expression of inflammation-related genes (iNOS, IL-1ꞵ, TNF-α) and increased the expression of antioxidant enzymes (Gpx-1 and SOD-1). The core genes HSP90AA1, Stat3, Mapk1, mTOR, Fyn, Ptk2b, and Lck were closely related to these beneficial effects of aloesone. Furthermore, immunofluorescence staining and flow cytometry data confirmed that aloesone significantly repressed the activation of mTOR, p-mTOR, and HIF-1α induced by LPS and inhibited the protein expression of TLR4, which is the target of LPS. In conclusion, aloesone demonstrated multiple protective effects against LPS-induced oxidative stress, inflammation, M1 polarization, and apoptosis in macrophages, suggesting its potential as a prodrug.
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Chheda, Milan, Jingxian Liu, Song Cao, Kathleen Imbach, Marina Gritsenko, Tung-Shing Lih, Jennifer Kyle, et al. "EPCO-53. MULTI-SCALE REGULATION OF SIGNALING CASCADES AND TUMOR EVOLUTION IN HIGH GRADE ASTROCYTOMAS." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v136. http://dx.doi.org/10.1093/neuonc/noad179.0515.
Abstract:
Abstract The National Cancer Institute Clinical Proteomic Atlas Consortium (CPTAC) herein reports our deep characterization of 228 grade IV IDH1 WT and mutant astrocytomas (including 28 matched primary and recurrent GBMs) using 15 proteogenomic and metabolomic platforms. Major advances over our first CPTAC GBM report (Wang et al., 2021, Cancer Cell), are the inclusion of many more samples including paired primary and recurrent tumors, application of new platforms, including glycoproteomics and targeted mass spectrometry methods, development and application of new computational techniques, and the integration of an atlas of experimentally determined, functional, kinase substrate interactions from Kinase Library. Paired primary-recurrent GBM analyses showed increased clonal diversity in recurrent tumors as a function of time, and treatment-induced mutation signatures. Proteomic and metabolomic analyses showed that different drivers can cause similar downstream effects. Only EGFR altered tumors were associated with dual EGFR glycosylation (N352 and N603) and EGFR phosphorylation (Y316) events. IDH1 mutation was associated with activated RTK signaling and decreased hypoxia pathway activities, concordant with epigenetic and metabolic profiles. Protein-protein interaction and kinase/phosphatase-substrate analyses uncovered detailed signaling events from different upstream drivers (e.g., EGFR, PDGFRA, and IDH1) converged through a PTPN11 hub to downstream effectors, including GAB1, IRS1, MAP3K5, and PTK2B. In summary, this multiscale resource presents new and deeper biological insights regarding treatment impact on tumor evolution, shared downstream consequences of independent drivers, and the potential importance of PTPN11 signaling circuitry across high-grade gliomas. We hope that reporting this new international resource to the SNO community will advance therapeutic development, including targeted therapies that may avoid known mechanisms of resistance.
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Wei, Yicong, Keming Qi, Yi Yu, Wei Lu, Wei Xu, Chengzi Yang, and Yu Lin. "Analysis of Differentially Expressed Genes in the Dentate Gyrus and Anterior Cingulate Cortex in a Mouse Model of Depression." BioMed Research International 2021 (February 11, 2021): 1–17. http://dx.doi.org/10.1155/2021/5013565.
Abstract:
Major depressive disorder (MDD) is a prevalent, chronic, and relapse-prone psychiatric disease. However, the intermediate molecules resulting from stress and neurological impairment in different brain regions are still unclear. To clarify the pathological changes in the dentate gyrus (DG) and anterior cingulate cortex (ACC) regions of the MDD brain, which are the most closely related to the disease, we investigated the published microarray profile dataset GSE84183 to identify unpredictable chronic mild stress- (UCMS-) induced differentially expressed genes (DEGs) in the DG and ACC regions. Based on the DEG data, functional annotation, protein-protein interaction, and transcription factor (TF) analyses were performed. In this study, 1071 DEGs (679 upregulated and 392 downregulated) and 410 DEGs (222 upregulated and 188 downregulated) were identified in DG and ACC, respectively. The pathways and GO terms enriched by the DEGs in the DG, such as cell adhesion, proteolysis, ion transport, transmembrane transport, chemical synaptic transmission, immune system processes, response to lipopolysaccharide, and nervous system development, may reveal the molecular mechanism of MDD. However, the DEGs in the ACC involved metabolic processes, proteolysis, visual learning, DNA methylation, innate immune responses, cell migration, and circadian rhythm. Sixteen hub genes in the DG (Fn1, Col1a1, Anxa1, Penk, Ptgs2, Cdh1, Timp1, Vim, Rpl30, Rps21, Dntt, Ptk2b, Jun, Avp, Slit1, and Sema5a) were identified. Eight hub genes in the ACC (Prkcg, Grin1, Syngap1, Rrp9, Grwd1, Pik3r1, Hnrnpc, and Prpf40a) were identified. In addition, eleven TFs (Chd2, Zmiz1, Myb, Etv4, Rela, Tcf4, Tcf12, Chd1, Mef2a, Ubtf, and Mxi1) were predicted to regulate more than two of these hub genes. The expression levels of ten randomly selected hub genes that were specifically differentially expressed in the MDD-like animal model were verified in the corresponding regions in the human brain. These hub genes and TFs may be regarded as potential targets for future MDD treatment strategies, thus aiding in the development of new therapeutic approaches to MDD.
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Pechanska, Paulina, Joachim Kunz, Tobias Rausch, Obul Reddy Bandapalli, Elena Orlova, Judit Sagi, Martin Stanulla, et al. "Gene Panel Sequencing of Primary and Relapsed Pediatric T-ALL Shows That Relapse-Specific Mutations Are Diverse and Mostly Non-Recurrent." Blood 126, no. 23 (December 3, 2015): 1428. http://dx.doi.org/10.1182/blood.v126.23.1428.1428.
Abstract:
Abstract Precursor T-cell acute lymphoblastic leukemia (T-ALL) remains one of the major challenges of pediatric oncology, because relapses are frequently refractory to treatment and fatal. We aimed at identifying relapse specific genetic alterations by analyzing a cohort of 147 primary T-ALL patients and of 70 relapsed T-ALL patients with targeted gene panel sequencing. In addition to the analysis of single nucleotide variants (SNVs) and small insertions and deletions (InDels), we made use of the available coverage data to characterize aberrant copy number alterations (CNA). DNA from bone marrow of these 217 pediatric T-ALL patients was analyzed by gene panel sequencing after target capture with Agilent HaloPlex. In the target capture design, exons of 324 genes were included that had been found before by whole exome sequencing to carry somatic mutations in a pilot set of relapsed T-ALL or that have been reported to be mutated in T-ALL in the literature. We did not analyze corresponding remission samples and did not discriminate between germline and somatic alterations. Only mutations with an allele frequency (AF) > 10% were considered and absence of the mutation in the 1000 Genomes variant catalogue was required. Copy number analysis based on read-depth data identified deletions (DEL) and amplifications (AMP). Direct comparison of CNAs by multiplex ligation-dependent probe amplification (MPLA) and gene panel sequencing was possible for 13 overlapping regions covering 14 genes in 185 samples. Recognition rate by coverage analysis was 98% (256/260) for biallelic alterations and 81% (92/114) for monoallelic alterations found by MLPA. On average, gene panel sequencing identified 6.7 mutations in initial diagnosis samples (SNVs: 5.2; InDels: 1.5) and 7.9 mutations in relapse samples (SNVs: 5.9; InDels: 2). In the group of primary leukemia and relapse samples, the average AMP/DEL per patient was 8.2 (AMP: 3.2, DEL: 5.0) and 8.8 (AMP: 4.2, DEL: 4.6), respectively. 31 genes were found to be mutated and 46 deleted/amplified in 10 or more patients (see Table 1 and 2). Table 1. Most commonly mutated genes (SNVs and InDels) Gene Total # of mutations # pts with mutation in primary T-ALL(n=147) # pts with mutation in relapsed T-ALL (n=70) NOTCH1 178 88 (60%) 38 (54%) PHF6 47 24 (16%) 16 (23%) FBXW7 42 20 (14%) 17 (24%) OBSCN 35 20 (14%) 10 (14%) DNM2 28 17 (12%) 10 (14%) PTEN 34 20 (14%) 4 (6%) XIRP2 24 19 (13%) 5 (7%) CDH23 23 11 (7%) 11 (16%) WT1 36 11 (7%) 8 (11%) NT5C2 22 1 (1%) 17 (24%) Table 2. Most common copy number alterations Amplifications Deletions Gene primary T-ALL (n=147) relapsed T-ALL (n=64) Gene primary T-ALL (n=147) relapsed T-ALL (n=64) MYB 9 (6%) 9 (15%) CDKN2A 102 (70%) 36 (59%) MYC 11 (8%) 6 (10%) CDKN2B 83 (57%) 31 (51%) NRG1 11 (8%) 3 (5%) MLLT3 28 (19%) 5 (8%) UNC5D 11 (8%) 3 (5%) PHIP 18 (12%) 6 (10%) NCOA2 11 (8%) 3 (5%) ELOVL4 18 (12%) 5 (8%) PTK2B 11 (8%) 3 (5%) MAP3K7 17 (12%) 5 (8%) FDFT1 11 (8%) 3 (5%) CASP8AP2 17 (12%) 5 (8%) ABL1 8 (5%) 3 (5%) APC 19 (13%) 3 (5%) CNOT3 8 (5%) 3 (5%) LEF1 16 (11%) 5 (8%) SMG8 3 (2%) 7 (10%) PAX5 15 (10%) 5 (8%) Potential novel mechanisms of oncogene activation are amplifications of PTK2B, a gene that has been found to be deregulated by fusion in Philadelphia-like BCP-ALL and that is potentially targetable by tyrosine kinase inhibitors, and of MYC, which has long been known to be a key player in T-ALL leukemogenesis and that is amplified in neuroblastoma and medulloblastoma. Enriched in relapse, we identified mutations in NT5C2 (p=1.4E-08), TP53 (p=0.0006) and CCDC88A (p=0.01), and amplifications of a region on chr 17q represented by the genes CLTC, ABCA5, C17orf80 and SRSF2. MLLT3 deletions were enriched in primary samples (p=0.04), consistent with the observation that MLLT3 deletions confer a lower risk of relapse in patients treated on BFM protocols. Conclusion Gene panel sequencing emerges as a suitable tool for a comprehensive genetic characterization of pediatric T-ALL. Within the group of selected genes contained in the panel, CNA were as frequent as point mutations. Only few genes were found to be specifically altered in relapse, indicating that progression to relapse may involve diverse, non-recurrent genetic alterations. Disclosures No relevant conflicts of interest to declare.
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Roberts, Kathryn G., Debbie Payne-Turner, Kelly McCastlain, Zhaohui Gu, Ilaria Iacobucci, Richard C. Harvey, I.-Ming Chen, et al. "High Frequency and Poor Outcome of Ph-like Acute Lymphoblastic Leukemia in Adults." Blood 126, no. 23 (December 3, 2015): 2618. http://dx.doi.org/10.1182/blood.v126.23.2618.2618.
Abstract:
Abstract Introduction: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. The prevalence of Ph-like ALL increases with age and accounts for over 25% of patients with B-progenitor ALL between the ages of 21-39 years. However, the frequency, outcome and genetic basis of Ph-like ALL in adults over the age of 39 is unknown. The goals of this study were to define the prevalence of Ph-like ALL across the adult age spectrum, assess response to conventional chemotherapy, and define the genetic landscape of Ph-like ALL in adults. Methods: We studied 692 adults with B-ALL obtained from multiple groups including the Alliance (Cancer and Leukemia Group B), ECOG-ACRIN, MD Anderson Cancer Center, Northern Italy Leukemia Group, Princess Margaret Cancer Centre, SWOG and UK NCRI. The cohort was divided into three age groups: 21-39 years (median age 28±6 years, n=333), 40-59 years (median age 47±6 years, n=246) and 60-79 years (median age 67±7 years, n=101). RNA samples were screened using a Taqman low density array (LDA) card that identifies patients with the Ph-like ALL gene signature, in addition to BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, MLL-rearranged and ERG altered ALL. Cytogenetic data was also available for the majority of cases. High expression of CRLF2 was determined by the LDA card, and CRLF2 rearrangement (IGH-CRLF2 or P2RY8-CFRLF2) was confirmed using fluorescence in situ hybridization. Total stranded transcriptome sequencing (RNA-seq) using the Illumina platform was performed on 99 cases and sequencing data was analyzed using FusionCatcher and CICERO. Results: The overall prevalence of ETV6-RUNX1, TCF3-PBX1 and ERG ALL in adults was low (1.3%, 3.6% and 3.1%, respectively), whilst the prevalence of patients with BCR-ABL1, Ph-like and MLL-rearranged ALL was 20%, 24% and 14%, respectively. Ph-like ALL comprised 26% of patients between 21-39 years of age and 20% of patients aged 40-79. Patients with BCR-ABL1 and Ph-like ALL presented with higher white blood counts at diagnosis compared to non Ph-like ALL patients (57.7 and 65.0 vs 28.5 x 109/L). Patients with Ph-like ALL were also more likely to be male compared to patients with BCR-ABL1 and non Ph-like ALL, with 66% vs 50% and 50%, respectively(p<0.0001; Fisher's exact test). The outcome of patients with Ph-like ALL was markedly inferior to other ALL subtypes (excluding patients with BCR-ABL1 and MLL rearrangement), with 5-year event free survival rates of 23.2±5.4 vs 51.2±4.7 (p<0.0001) and overall survival rates of 26.5±5.5 vs 56.3±4.6 (p<0.0001). We then characterized the kinase-activating alterations in adult Ph-like ALL. Similar to previous reports, 99 of 186 (53%) of patients with Ph-like ALL had high expression of CRLF2. Of 75 cases tested, 56 harbored IGH-CRLF2 and 19 P2RY8-CRLF2. Of the 87 Ph-like ALL patients with low CRLF2 expression, we identified rearrangements involving tyrosine kinase or cytokine receptor genes in 45 patients: ABL1 (n=5 patients), ABL2 (n=7), CSF1R (n=1), EPOR (n=8), JAK2 (n=18), PDGFRA (n=1), PDGFRB (n=2), PTK2B (n=1) and TYK2 (n=2). Nine of these 45 fusions have not previously been identified in Ph-like ALL including MEF2D-CSF1R, HMBOX1-JAK2, SMU1-JAK2, SNX29-JAK2 (n=2 patients), ZNF340-JAK2, FIP1L1-PDGFRA, TMEM2-PTK2B and ZNF340-TYK2. Exome sequencing is being performed on cases that do not harbor a kinase fusion by RNA-seq analysis. Conclusion: Ph-like ALL is common across the age spectrum of adult ALL, comprising over 20% of patients from ages 21-79 years, with a notably high prevalence of fusions involving JAK2. These findings warrant the development of clinical trials that assess the efficacy of tyrosine kinase inhibitors to improve the treatment outcome, similar to those that are being established for pediatric ALL. Disclosures Fielding: Amgen: Consultancy, Honoraria. Rowe:Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Mullighan:Amgen: Honoraria; Incyte: Consultancy.
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Xiang, Xin, Xuan Huang, Jianfeng Wang, Haiyang Zhang, Wei Zhou, Chunhui Xu, Yunyan Huang, Yuting Tan, and Zhaozheng Yin. "Transcriptome Analysis of the Ovaries of Taihe Black-Bone Silky Fowls at Different Egg-Laying Stages." Genes 13, no. 11 (November 8, 2022): 2066. http://dx.doi.org/10.3390/genes13112066.
Abstract:
The poor egg-laying performance and short peak egg-laying period restrict the economic benefits of enterprises relating to the Taihe black-bone silky fowl. Ovaries are the main organ for egg production in poultry. Unlike that of mammals, the spawning mechanism of poultry has rarely been reported. As a prominent local breed in China, the reproductive performance of Taihe black-bone silky fowls is in urgent need of development and exploitation. To further explore the egg-laying regulation mechanism in the different periods of Taihe black-bone silky fowls, the ovarian tissues from 12 chickens were randomly selected for transcriptome analysis, and 4 chickens in each of the three periods (i.e., the pre-laying period (102 days old, Pre), peak laying period (203 days old, Peak), and late laying period (394 days old, Late)). A total of 12 gene libraries were constructed, and a total of 9897 differential expression genes (DEGs) were identified from three comparisons; the late vs. peak stage had 509 DEGs, the pre vs. late stage had 5467 DEGs, and the pre vs. peak stage had 3921 DEGs (pre-stage: pre-egg-laying period (102 days old), peak-stage: peak egg-laying period (203 days old), and late-stage: late egg-laying period (394 days old)). In each of the two comparisons, 174, 84, and 2752 differentially co-expressed genes were obtained, respectively, and 43 differentially co-expressed genes were obtained in the three comparisons. Through the analysis of the differential genes, we identified some important genes and pathways that would affect reproductive performance and ovarian development. The differential genes were LPAR3, AvBD1, SMOC1, IGFBP1, ADCY8, GDF9, PTK2B, PGR, and CD44, and the important signaling pathways included proteolysis, extracellular matrices, vascular smooth muscle contraction, the NOD-like receptor signaling pathway and the phagosome. Through the analysis of the FPKM (Fragments Per Kilobase of exon model per Million mapped fragments) values of the genes, we screened three peak egg-laying period-specific expressed genes: IHH, INHA, and CYP19A1. The twelve genes and five signaling pathways mentioned above have rarely been reported in poultry ovary studies, and our study provides a scientific basis for the improvement of the reproductive performance in Taihe black-bone silky fowls.