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1
Donadoni, Carla, Rocco Piazza, Diletta Fontana, Andrea Parmiani, Alessandra Pirola, Sara Redaelli, Giovanni Signore, et al. "Evidence of ETNK1 Somatic Variants in Atypical Chronic Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 2212. http://dx.doi.org/10.1182/blood.v124.21.2212.2212.
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Abstract Atypical Chronic Myeloid Leukemia (aCML) is a clonal disorder belonging to the Myeloproliferative/Myelodysplastic (MPN/MDS) group. The molecular lesions responsible for the onset of aCML remained unknown until 2013 when recurrent somatic mutations of SETBP1 were identified. However, the frequency of SETBP1 mutations in aCML does not exceed 25-30%, which suggests that other lesions may play a role in the remaining cases. To gain further insight into the somatic variants responsible for the onset of aCML, we generated whole-exome and transcriptome sequencing data on 15 matched case/control aCML samples. A total of 151 non-synonymous and 42 synonymous single-nucleotide somatic variants were identified. Of these, 140 were transitions and 53 transversions. Of the non-synonymous mutations, 141 were missense and 10 nonsense mutations. In 2/15 (13.3%) samples we identified the presence of missense, single-nucleotide somatic variants occurring in the ETNK1 gene affecting two contiguous residues: H243Y and N244S. Sanger sequencing confirmed the presence and the somatic nature of the variants. Targeted resequencing of 383 clonal hematological disorders showed evidence of mutated ETNK1 in 7/70 aCML (10.0%, 95% C.I. 4.6-19.5%) and in 2/77 chronic myelomonocytic leukemia samples (CMML; 2.6%, 95% C.I. 0.2-9.5%) %), while no ETNK1 mutations were identified in the remaining hematological disorders. All the variants were heterozygous and clustered in the same, highly conserved region within the kinase domain (1/9 H243Y and 8/9 N244S). Somatic, heterozygous ETNK1 variants have been also recently reported in 10% of Systemic Mastocytosis (SM) cases and in 22% of SM with associated hypereosinophilia (Lasho T et al., Abstract 4062, EHA2014); strikingly, there is a large overlap between the variants that we identified in aCML and CMML and those described for SM (3 N244S and 2 G245A), which suggests that the common hotspot region may play a critical and yet unknown functional role. The hitherto described data suggest that ETNK1 variants are restricted to a limited subset of hematological disorders. This is further supported by the lack of somatic ETNK1 mutations in 60 paired whole-genome and over 600 exomes, comprising 276 paired tumor/germline primary samples and 344 cancer cell lines (http://cancer.sanger.ac.uk/cancergenome/projects/cell_lines/). In 2/6 ETNK1 mutated aCML cases (33%, 95% C.I. 9%-70%), we detected the presence of a coexisting somatic SETBP1 variant. The fraction of SETBP1 mutations identified in this group is perfectly in line with the overall frequency of SETBP1 mutations in aCML, suggesting that mutations occurring in ETNK1 and SETBP1 are not mutually exclusive. To discriminate if ETNK1 and SETBP1 mutations occur in different or in the same clone, we performed colony assay experiments, revealing the coexistence of the two somatic mutations within the same clone. Liquid Chromatography – Mass Spectrometry experiments revealed that in ETNK1 mutated cells the intracellular levels of phosphoethanolamine are over 5-fold lower than in the wild-type counterpart (p < 0.05), suggesting that ETNK1 mutations may impair the physiological catalytic activity of the kinase. Taken globally these data identify ETNK1 somatic mutations as a new oncogenic lesion in aCML and CMML, two overlapping MDS/MPN neoplasms. They also show that ETNK1 variants apparently cause a loss-of-function effect, leading to a decrease in the intracellular levels of phosphoethanolamine. Disclosures Campbell: 14M Genomics Limited: Consultancy, Equity Ownership.
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Fontana, Diletta, Mario Mauri, Rossella Renso, Mattia Docci, Ilaria Crespiatico, Lisa M. Røst, Mi Jang, et al. "ETNK1 Mutations in Atypical Chronic Myeloid Leukemia Induce a Mutator Phenotype That Can be Reverted with Phosphoethanolamine." Blood 136, Supplement_2 (November 19, 2020): LBA—5—LBA—5. http://dx.doi.org/10.1182/blood-2020-143852.
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ETNK1 kinase is responsible for the phosphorylation of ethanolamine to phosphoethanolamine (P-Et) (Kennedy, 1956, J Biol Chem). Recurrent somatic mutations occurring on ETNK1 were identified in about 13% of patients affected by atypical chronic myeloid leukemia (aCML), in 3-14% of chronic myelomonocytic leukemia (CMML), and in 20% of systemic mastocytosis (SM) patients with eosinophilia (Gambacorti-Passerini, 2015, Blood; Lasho, 2015, Blood Cancer J). ETNK1 mutations, encoding for H243Y, N244S/T/K, and G245V/A amino acid substitutions, cluster in a very narrow region of the ETNK1 catalytic domain and cause an impairment of ETNK1 enzymatic activity leading to a significant decrease in the intracellular concentration of P-Et (Gambacorti-Passerini, 2015, Blood). Despite this evidence, however, their oncogenic role remained largely unexplained. Here, we investigated the specific role of these mutations by using cellular CRISPR/Cas9 and ETNK1 overexpression models as well as aCML patients' samples. We showed that mutated ETNK1 causes a significant increase in mitochondrial activity (1.87 fold increase compared to WT; p=0.0002) and in ROS production (2.05 fold increase compared to WT; p<0.0001). Since ROS are responsible for DNA oxidative damage, we firstly generated ChIP-Seq data for ETNK1 mutated cells using an antibody raised against the oxoguanine (oxoG) and we compared oxoG signal against the wild-type cell line, to assess whether ETNK1 mutations could cause accumulation of DNA lesions. This analysis revealed a significant increase in oxoG in mutated cells, compared to WT (p=0.018). Then, we investigated if these lesions were driving the onset of a mutator phenotype by applying the 6-thioguanine (6-TG) resistance assays to our cell models, showing that in the mutated cells there was a 5.4 fold increase in colony number compared to the WT line (p<0.0001). Moreover, we investigated if the ROS-mediated genotoxic insult operating in ETNK1-mutated lines could be also associated with an increase in DNA double-strand breaks. Comparison of ETNK1-N244S and ETNK1-WT lines revealed a sharp increase in the number of γH2AX foci (2.52 fold increase; p=0.0002) in the former. At this point, we hypothesized that the decreased P-Et concentration in ETNK1-mutated cells could be responsible for the increased mitochondrial activity. ETNK1-N244S cells treated with P-Et showed a complete restoration of the normal mitochondrial membrane potential and generation of ROS. Moreover, the mutator phenotype was reverted by P-Et treatment, supporting the hypothesis of a direct involvement of P-Et in the induction of DNA damage. To dissect the mechanism by which P-Et intracellular levels were able to control mitochondria activity, we isolated the mitochondrial oxidative phosphorylation complexes I to IV and we measured the activity of each complex in absence/presence of increasing P-Et concentrations. This approach revealed a profound, dose-dependent decrease in redox activity for mitochondrial complex II (P-Et 10μM: 1.80 fold decrease; p=0.0012; P-Et 20μM: 7.40 fold decrease; p<0.0001; P-Et 50μM: 28.85 fold decrease; p<0.0001) and virtually no effect for the other three complexes, indicating that P-Et controls mitochondria potential through direct inhibition of complex II. To gain insight into the specific mechanism by which P-Et could repress complex II, we analyzed its activity in competition assays in presence of both P-Et and increasing concentration of succinate, the endogenous substrate of succinate dehydrogenase (SDH), showing that succinate supplementation was able to restore the normal SDH activity starting from 50µM. Taken globally, these data suggest that P-Et acts as a competitive inhibitor of succinate for SDH activity. In line with these data, automatic docking of P-Et inside the SDH catalytic domain confirmed that P-Et can occupy the succinate binding site in an energetically favorable conformation, mimicking succinate. In conclusion, the reduced activity of mutant ETNK1 leads to the accumulation of new mutations through the reduced competition of P-Et with succinate, increased mitochondrial activity and ROS production. This mechanism can be blocked, at least in vitro, by P-Et supplementation, suppressing the accumulation of new mutations mediated by the ETNK1-dependent mutator phenotype. In vivo studies will address the therapeutic potential of P-Et. Disclosures Rea: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.
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Gambacorti-Passerini, Carlo B., Carla Donadoni, Andrea Parmiani, Alessandra Pirola, Sara Redaelli, Giovanni Signore, Vincenzo Piazza, et al. "Recurrent ETNK1 mutations in atypical chronic myeloid leukemia." Blood 125, no. 3 (January 15, 2015): 499–503. http://dx.doi.org/10.1182/blood-2014-06-579466.
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Key Points Whole-exome sequencing reveals the presence of recurrent somatic mutations of ETNK1 in patients with atypical chronic myeloid leukemia. ETNK1 mutations impair the catalytic activity of the enzyme, causing a decrease in the intracellular levels of phosphoethanolamine.
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Niro, Antonio, Rocco Piazza, Gabriele Merati, Alessandra Pirola, Carla Donadoni, Diletta Fontana, Sara Redaelli, et al. "ETNK1 Is an Early Event and SETBP1 a Late Event in Atypical Chronic Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 3652. http://dx.doi.org/10.1182/blood.v126.23.3652.3652.
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Abstract Atypical Chronic Myeloid Leukemia (aCML) is a clonal disorder belonging to the myelodisplastic-myeloproliferative neoplasms, according to the WHO-2008 classification. From a clinical point of view it closely resembles the classical Chronic Myeloid Leukemia (CML), however it lacks the presence of the Philadelphia chromosome and of the BCR-ABL1 fusion gene. In recent works, we and others characterized the somatic lesions present in the aCML genome, mainly by using Next Generation Sequencing (NGS) technologies, demonstrating the presence of a large set of recurrent somatic mutations involving, among the others, SETBP1, ETNK1, ASXL1, EZH2, CBL, TET2, NRAS and U2AF1 genes. The identification of somatic variants occurring in a large number of genes clearly indicates that the genetic bases of aCML are very heterogeneous, in striking contrast with classical CML. This heterogeneity poses a great challenge to the dissection of the molecular steps required for aCML leukemogenesis. The hierarchical reconstruction of the different mutations occurring in a clonal disorder can have important biological, prognostic and therapeutic repercussions; therefore we started a project focused on the dissection of the aCML clonal evolution steps through the analysis of individual leukemic clones by methylcellulose assays in samples whose mutational status has been previously characterized by matched whole-exome sequencing. Patient CMLPh-019 was characterized by the presence of a complex mutational status, with somatic variants occurring in SETBP1, ETNK1, ASXL1 and CBL genes (Fig. 1a). Targeted resequencing analysis of individual clones revealed the presence of all the 4 variants in 44/60 (73.3%) clones; in 15/60 (25%) we detected the presence of mutated ETNK1, ASXL1 and CBL and wild-type (WT) SETBP1. Of these 15 clones, 33% carried heterozygous and 67% homozygous CBL mutations. In one clone (1.7%) we detected heterozygous ETNK1, homozygous CBL and WT sequences for ASXL1 and SETBP1, suggesting a strong selective pressure towards the acquisition of homozygous CBL mutations. Identification of homozygous CBL mutations in all the main clonal phases suggests that a significant positive selective pressure is associated with this event. Allelic imbalance analysis of CMLPh-019 exome using CEQer revealed that CBL homozygosity is caused by a somatic uniparental disomy event occurring in the telomeric region of the long arm of chromosome 11. Patient CMLPh-005 (Fig. 1b) was mutated in ASXL1, CBL and SETBP1. Targeted analysis done on 68 clones revealed a complex, branching evolution, with 63 clones carrying all the 3 variants. Of them, 47 (74.6%) had a heterozygous and 16 (25.4%) a homozygous CBL variant. Four clones (4.2%) carried ASXL1 and SETBP1 but not CBL mutations, while 1 clone was mutated in ASXL1 and CBL in absence of SETBP1 mutations, which suggests that CBL mutations occurred independently in two different subclones. Also in this case, allelic imbalance analysis of exome data revealed that CBL homozygosity was caused by a telomeric somatic uniparental disomy event. According to exome sequencing, patient CMLPh-003 carried SETBP1 mutation G870S and NRAS variant G12R. Clonal analysis confirmed the presence of SETBP1 G870S in all the clones analyzed, while heterozygous NRAS G12R mutation was detected in 67% (Fig. 1c). Notably in the remaining 33% another heterozygous NRAS variant, G12D, was detected. Retrospective reanalysis of exome data confirmed the presence of the newly identified variant, which had been previously filtered-out from exome data because of the low frequency. Patient CMLPh-013 was mutated in ASXL1, ETNK1, NRAS and SETBP1. Of the 39 clones analyzed, 34 (82.9%) showed the coexistence of ASXL1, ETNK1, NRAS and SETBP1, 4 were mutated in ASXL1, ETNK1 and NRAS and 1 in ETNK1 and NRAS, suggesting that ETNK1 and NRAS were early events, ASXL1 an intermediate one and SETBP1 a late variant (Fig. 1d). Taken globally, these data indicate that ETNK1 variants occur very early in the clonal evolution history of aCML, while ASXL1 represents an early/intermediate event and SETBP1 is often a late event. They also suggest that, in the context of aCML, there is a strong selective pressure towards the accumulation of homozygous CBL variants, as already shown in other leukemias. Figure 1. Clonal analysis of four aCML cases. The asterisks indicate hypothetical clones. Figure 1. Clonal analysis of four aCML cases. The asterisks indicate hypothetical clones. Disclosures Rea: Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria.
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Kosmider, Olivier. "Mutations of ETNK1 in aCML and CMML." Blood 125, no. 3 (January 15, 2015): 422–23. http://dx.doi.org/10.1182/blood-2014-11-609057.
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Okuda, Rurika, Yasuhito Nannya, Yotaro Ochi, Maria Creignou, Hideki Makishima, Tetsuichi Yoshizato, Yasunobu Nagata, et al. "Der(1;7)(q10;p10) Presents with a Unique Genetic Profile and Frequent ETNK1 Mutations in Myeloid Neoplasms." Blood 138, Supplement 1 (November 5, 2021): 1513. http://dx.doi.org/10.1182/blood-2021-149556.
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Abstract Background Der(1;7)(q10;p10) (der(1;7) is an unbalanced translocation recurrently found in myeloid neoplasms, particularly in myelodysplastic syndromes (MDS) and related disorders. Caused by a recombination between two homologous alphoid sequencing D1Z7 and D7Z1 on chromosomes 1 and 7, respectively, it results in monosomy 7q and trisomy 1q, which is implicated in the pathogenesis of der(1;7)-positive myeloid neoplasms. Previous studies reported frequent co-occurrence of +8 and del(20q), as well as RUNX1 mutations, the genetic and clinical characteristics of this abnormality has not fully been elucidated. Methods In this study, we enrolled a total of 153 cases myeloid neoplasms positive for der(1;7) from Japanese and German cohorts, in which co-occurring genetic lesions were analyzed using whole exome and/or targeted-capture sequencing. An additional 3,223 MDS and related neoplasm cases were also analyzed using targeted-capture sequencing to identify der(1;7)-specific genomic features. Results Ethnicity was evaluated comparing the frequency of der(1;7) in 944 German MDS cases and 763 Japanese MDS cases. Der(1;7) cases were observed at a higher frequency in Japanese MDS cohort compared to German MDS cohort (73/763 cases versus 4/944 cases, p < 0.00001). Der(1;7) cases showed a strong male predominance (86.3%) (p<0.001). Of 153 myeloid neoplasm patients harboring der(1;7), 114 were diagnosed with MDS, 28 with AML, 5 with MDS-MPN and 1 with MPN. Targeted-capture sequencing revealed mutations in common myeloid drivers (n=61) in 96% of der(1;7) cases. The most frequently mutated gene was RUNX1 with 46%, followed by ETNK1 (24.5%) and EZH2 (24.5%). Of interest, ETNK1 mutation was identified as the most unique to der(1;7) when compared to myeloid neoplasm cases without der(1;7) (n=3,066) [odds ratio (OR)=15.06], followed by ETV6 (OR=9.35) and EZH2 (OR=6.52). To further examine the uniqueness of this mutation profile, the mutational profile of der(1;7) was compared to those myeloid neoplasm cases harboring amp(1q) (n=52) and monosomy 7 (n=105). Highly frequent ETV6 and ETNK1 mutations were highly unique to der(1;7) cases when compared to amp(1q) cases (OR=3.72, OR=2.57, respectively). BCOR and ETNK1 mutations were highly unique to der(1;7) cases when compared to monosomy 7 cases (OR=35.88, OR=4.29, respectively). Both amp(1q) and monosomy 7 cases showed a higher mutation rate in TP53 compared to der(1;7) cases (49.1% and 51%, respectively, vs 3.5 %) . From these mutational characteristics, ETNK1 was identified as being the most unique to der(1;7) when compared to amp(1q), monosomy 7 and other myeloid neoplasm cases. ETNK1-mutated der(1;7) cases were featured with eosinophilia (p < 0.0005), a lack of RAS pathway mutations and trisomy 8 when compared to ETNK1-wild type der(1;7) cases. Survival analysis was conducted to elucidate the difference in survival in der(1;7) cases (n=65) versus myeloid neoplasm cases (n=2066). Der(1;7)-harboring myeloid neoplasm cases had a median overall survival of 6.8 months (95% CI, 3.5 to 11.9) and non-der(1;7) harboring myeloid neoplasm cases were 11.8 months (95% CI, 10.5 to 12.6). Thus, der(1;7)-harboring myeloid neoplasm cases had poorer prognosis (p<0.001). Conclusion In conclusion, der(1;7) is an unbalanced translocation that occurs predominantly in males and is seen more frequently in Japanese than Caucasian populations. Der(1;7) cases present with a mutational profile that is distinct from other myeloid neoplasm cases such as those with amp(1q) and monosomy7/del(7q), showing frequency of ETNK1 mutations. Disclosures Nannya: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Speakers Bureau; Astellas: Speakers Bureau. Kern: MLL Munich Leukemia Laboratory: Other: Part ownership. Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Atsuta: Astellas Pharma Inc.: Speakers Bureau; Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria. Handa: Ono: Honoraria; BMS: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding. Ohyashiki: Novartis Pharma: Other: chief clinical trial; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Ogawa: Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Kan Research Laboratory, Inc.: Consultancy, Research Funding; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; ChordiaTherapeutics, Inc.: Consultancy, Research Funding; Ashahi Genomics: Current holder of individual stocks in a privately-held company.
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Okuda, Rurika, Hideki Makishima, Yasuhito Nannya, Yotaro Ochi, Tetsuichi Yoshizato, Yasunobu Nagata, Kenichi Yoshida, et al. "Distinct, Ethnic, Clinical, and Genetic Characteristics of Myelodysplastic Syndromes with Der(1;7)." Blood 134, Supplement_1 (November 13, 2019): 5392. http://dx.doi.org/10.1182/blood-2019-129943.
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der(1;7)(q10;p10) is a recurrent chromosomal abnormality found in a wide variety of myeloid neoplasms observed in as high as 6% of myelodysplastic syndromes (MDS) in Asian populations, while rarely observed in Caucasian populations. It is thought to be generated by a recombination between two highly homologous centromere alphoid sequences which lead to an unbalanced abnormality of monosomy of 7q and trisomy of 1q. However, despite the presence of -7q, der(1;7) has been associated with a better prognosis compared to monosomy 7 or other del(7q) (-7/del(7q)). In addition to its association with +8 and del(20q), frequent RUNX1 mutations and a paucity of mutated TP53 have been reported in der(1;7) tumors, but otherwise, the molecular features of this abnormality have been poorly characterized in the literature. This is most likely because it is very rare in Caucasians, even though it represents one of the most prevalent lesions among Asian populations. The purpose of our study is to clarify the frequency and mutational landscape of der(1;7) in myeloid neoplasms on the basis of targeted-capture sequencing. A total of 1,707 MDS cases, including 944 German and 763 Japanese cases, were enrolled, from which we identified 73 (4.0%) cases with der(1;7). The prevalence was >20 times higher in Japanese (9.0%) than German (0.43%) cohorts (p<0.0001). We also identified a strong male predominance in der(1;7)-positive cases (90.4%) compared to negative cases. Also including an additional 22 cases, somatic mutations and copy number abnormalities in der(1;7) were interrogated in a total of 95 cases, which included 84 (88.4%) with MDS, 9 (9.5%) with AML, and 2 (2.1%) with MPN. Among MDS patients, 29 were low-risk, 47 were high-risk, and the rest were not specified. In mutation analysis, at least one mutation was detected in 98% of der(1;7) cases, most frequently affecting RUNX1 (42%), followed by EZH2 (26%), and ETNK1 (25%). Copy number analysis showed a high frequency of del(20q) and trisomy 8 in der(1;7) cases: 27.4% and 18.9% respectively. On the basis of mutant cell fractions, most of these mutations were present in subclones acquired within the major population harboring der(1;7). In particular, most of the EZH2 (7q35-q36) mutations were thought to be secondary events in der(1;7)-positive cases, while representing initial events acquired before UPD(7q) or -7/del(7q) in der(1;7)-negative cases. Of interest, der(1;7) was associated with a low frequency of TP53 mutations, which were seen only in 3% of cases with der(1;7), whereas highly prevalent in non-der(1;7) cases with -7/del(7q) (52%), which is concordant with a better clinical outcome was observed in der(1;7) cases compared with non-der(1;7) cases with monosomy 7 or other del(7q). Another unique feature of der(1;7) positive MDS was an extremely high frequency of RUNX1 mutations. However, the most prominent finding with secondary mutations in der(1;7) cases is the frequent hot spot mutation in ETNK1, which were originally reported in 8.8% of myeloid neoplasms with MPN features, like SETBP1 mutations. ENTK1 mutations were found in as many as 25% (23/95) of der(1;7) cases, while rarely seen in -7/del(7q) (1/89) (p<0.0001) or amp(1q) (2/68) (p=0.0001). Despite the high frequency of trisomy 8 observed in der(1;7) cases, none were associated with ETNK1 mutations. In addition, all of the RAS pathway mutations (positive in 16 cases) were observed in der(1;7) cases with wild-type ETNK1, while none were in ETNK1-mutant cases. Morphologically, these ETNK1-mutated der(1;7) cases presented with an increased eosinophil count in peripheral blood (760.9/ul vs. 78.1/ul) (p<0.001), compared to those without EKNK1 mutations, suggesting that ENTK1-mutated der(1;7) cases represent a novel disease entity within der(1;7), characterized by unique genetic features and increased eosinophils. In conclusion, der(1;7) is a genetically and clinically distinct subset of myeloid neoplasms, which showed unique features that are distinct from MDS cases in -7 and other del(7q). Especially, ETNK1 mutations subdivided cases with der(1;7) into two groups of genetically distinct subsets as shown in Figure 1. In the future, inhibition of the kinase activity in ETNK1 could be a novel therapeutic strategy in such a previously unrecognized subset as characterized by der(1;7) and eosinophilia. Figure 1 Disclosures Kern: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Baer:MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Atsuta:Janssen Paharmaceutical K.K.: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Handa:Ono: Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Ogawa:Qiagen Corporation: Patents & Royalties; Kan Research Laboratory, Inc.: Consultancy; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; Asahi Genomics: Equity Ownership; RegCell Corporation: Equity Ownership.
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Huang, Keng-Shiang, Yi-Ting Wang, Omkar Byadgi, Ting-Yu Huang, Mi-Hsueh Tai, Jei-Fu Shaw, and Chih-Hui Yang. "Screening of Specific and Common Pathways in Breast Cancer Cell Lines MCF-7 and MDA-MB-231 Treated with Chlorophyllides Composites." Molecules 27, no. 12 (June 20, 2022): 3950. http://dx.doi.org/10.3390/molecules27123950.
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Our previous findings have shown that the chlorophyllides composites have anticancer activities to breast cancer cell lines (MCF-7 and MDA-MB-231). In the present study, microarray gene expression profiling was utilized to investigate the chlorophyllides anticancer mechanism on the breast cancer cells lines. Results showed that chlorophyllides composites induced upregulation of 43 and 56 differentially expressed genes (DEG) in MCF-7 and MDA-MB-231 cells, respectively. In both cell lines, chlorophyllides composites modulated the expression of annexin A4 (ANXA4), chemokine C-C motif receptor 1 (CCR1), stromal interaction molecule 2 (STIM2), ethanolamine kinase 1 (ETNK1) and member of RAS oncogene family (RAP2B). Further, the KEGG annotation revealed that chlorophyllides composites modulated DEGs that are associated with the endocrine system in MCF-7 cells and with the nervous system in MDA-MB-231 cells, respectively. The expression levels of 9 genes were validated by quantitative reverse transcription PCR (RT-qPCR). The expression of CCR1, STIM2, ETNK1, MAGl1 and TOP2A were upregulated in both chlorophyllides composites treated-MCF-7 and MDA-MB-231 cells. The different expression of NLRC5, SLC7A7 and PKN1 provided valuable information for future investigation and development of novel cancer therapy.
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Fontana, Diletta, Carlo Gambacorti-Passerini, and Rocco Piazza. "Impact of ETNK1 somatic mutations on phosphoethanolamine synthesis, ROS production and DNA damage." Molecular & Cellular Oncology 8, no. 2 (February 19, 2021): 1877598. http://dx.doi.org/10.1080/23723556.2021.1877598.
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Fontana, Diletta, Daniele Ramazzotti, Andrea Aroldi, Antonio Niro, Luca Massimino, Delphine Rea, Fabio Stagno, et al. "Integrated Genomic, Functional and Prognostic Characterization of Atypical Chronic Myeloid Leukemia (aCML) in a Cohort of 43 Patients." Blood 134, Supplement_1 (November 13, 2019): 1714. http://dx.doi.org/10.1182/blood-2019-126467.
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Atypical chronic myeloid leukemia (aCML) is a rare BCR-ABL1 negative clonal disorder, which belongs to the myelodysplastic/myeloproliferative group. This disease is characterized by recurrent somatic mutations in several genes including SETBP1, ASXL1 and ETNK1, as well as high genetic heterogeneity, thus posing a great therapeutic challenge. The clinical prognosis for aCML is poor, with a median overall survival of 18 months after diagnosis, and no established standards of care exist for its treatment. The dissection of the molecular processes underlying aCML leukemogenesis could therefore result decisive in ameliorating the prognosis for aCML. With the aim to provide a comprehensive genomic characterization of aCML and to link the detected alterations with the clinical course of the disease, we applied a high-throughput sequencing strategy to 43 aCML samples, including whole-exome sequencing and RNA sequencing. Our study confirms ASXL1 and SETBP1 as the most frequently mutated genes with a total of 43.2% and 30.2%, respectively; ETNK1 mutations are observed in 14% of patients. An average of 2 mutations per patient was observed [range: 0-5]. We characterized the clonal architecture in a subset of 8 aCML patients by means of colony assays and targeted resequencing. The results indicate that ETNK1 variants occur very early in the clonal evolution history of aCML, while SETBP1 mutations represent a late event; interestingly, in the two cases where ASXL1 was mutated together with SETBP1, its mutations occupied an intermediate hierarchical position. CBL mutations, when present, showed a tendency toward reaching homozygosity through somatic uniparental disomy. Stratification based on RNA-sequencing gene expression data (Ramazzotti, Daniele, et al. Nature communications 9.1 (2018): 4453) identified two clearly different populations (26 and 17 patients) in terms of Overall Survival (OS), with 2 year OS of 69.23% [95% IC: 48.21%-86.67%] and 35.29% [95% IC: 14.21%-61.67%] respectively (logrank test for trend: p=0.004, Fig. 1A). In addition, the group with better prognosis showed a higher frequency of ETNK1 mutations (hypergeometric test: p=0.032). We next performed differential gene expression analysis to detect genes differentially expressed between the two patients' populations. This analysis revealed 38 significant genes (t-test p-value adjusted for false discovery rate p<0.01) overexpressed in the group with negative outcome. Notably, the majority of these genes are known cancer drivers, such as IDH2, MEN1, MYC and TP53. Involved pathways include gene transcription and cell differentiation, mitochondrial activity and DNA repair. We then considered RNA-sequencing data for the 4 most significant genes within the previous list (namely DNPH1, GFI1B, PARP1 and POLRMT) to build a classifier capable of associating patients to the respective subtype (better vs. worse prognosis). Our results show that a random forest classifier (Ho, Tin Kam. Proceedings of 3rd international conference on document analysis and recognition. Vol. 1. IEEE, 1995) using the 4 most significant genes achieves a 93.79% accuracy assessed by means of 10 fold cross validation (Fig.1B-C). In conclusion, we present here the first description of a large aCML cohort, in which sequencing data, clonal hierarchy of mutations and gene expression profiles were integrated through bioinformatics analysis. RNA-sequencing data stratification characterizes two groups with different prognosis; a classifier based on the 4 top differently expressed genes accurately predicts patients' outcome. Figure 1. A) Overall Survival curve (Kaplan-Meier curve) at 24 months shows significant different outcomes (p=0.004). B) Random forest classifiers learn multiple decision trees in order to predict outcomes. In the figure, an example of decision tree where nodes are genes and leaves are outcomes (better/worse prognosis). C) Heatmap of expression fold change for the top four differentially expressed genes. Figure 1 Disclosures Rea: BMS: Honoraria; Incyte Biosciences: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stagno:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Meyers Squibb: Consultancy.
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Lasho, T. L., C. M. Finke, D. Zblewski, M. Patnaik, R. P. Ketterling, D. Chen, C. A. Hanson, A. Tefferi, and A. Pardanani. "Novel recurrent mutations in ethanolamine kinase 1 (ETNK1) gene in systemic mastocytosis with eosinophilia and chronic myelomonocytic leukemia." Blood Cancer Journal 5, no. 1 (January 2015): e275-e275. http://dx.doi.org/10.1038/bcj.2014.94.
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Li, Li, Yi-Ping Mou, Yuan-Yu Wang, Hui-Ju Wang, and Xiao-Zhou Mou. "miR-199a-3p targets ETNK1 to promote invasion and migration in gastric cancer cells and is associated with poor prognosis." Pathology - Research and Practice 215, no. 9 (September 2019): 152511. http://dx.doi.org/10.1016/j.prp.2019.152511.
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Crisà, Elena, Maura Nicolosi, Valentina Ferri, Chiara Favini, Gianluca Gaidano, and Andrea Patriarca. "Atypical Chronic Myeloid Leukemia: Where Are We Now?" International Journal of Molecular Sciences 21, no. 18 (September 18, 2020): 6862. http://dx.doi.org/10.3390/ijms21186862.
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Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (>20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (< 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options.
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Chang, H., S. Y. Rha, H. Jeung, J. Ahn, J. Jung, T. Kim, H. Kwon, B. Kim, and H. C. Chung. "Gene-expression profiles related to a synergistic effect of taxane and suberoylanilide hydroxamic acid combination treatment in gastric cancer cells." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 50. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.50.
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50 Background: We evaluated the cytotoxic effects of combining of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, with taxanes in human gastric cancer cell lines, and evaluated the pre-treatment difference of gene profile to identify genes that could potentially mediate the cytotoxic response. Methods: Twenty-five gastric cancer cell lines with 22K gene expression data were treated with SAHA and paclitaxel or docetaxel, and the synergistic interaction between the drugs was evaluated in vitro using the combination index (CI) method. We performed significance analysis of microarray (SAM) to identify chemosensitivity-related genes in gastric cancer cell lines that were concomitantly treated with SAHA and taxane. We generated a correlation-matrix between gene expression and CI values to identify genes whose expression correlated with a combined effect of taxanes and SAHA. Results: Taxane and SAHA combination had a synergistic cytotoxic effect against taxane-resistant gastric cancer cells. We selected 49 chemosensitivity-related genes, which were commonly identified in paclitaxel and docetaxel combined with SAHA, via SAM analysis. Among them, nine common genes (SLIT2, REEP2, EFEMP2, CDC42SE1, FSD1, POU1F1, ZNF79, ETNK1, and DOCK5) were extracted from the subsequent correlation-matrix analysis. Conclusions: Taxane and SAHA combination could be efficacious for the treatment of gastric cancer. The genes which were related with the synergistic response to taxane and SAHA could serve as surrogate biomarkers to predict the therapeutic response in gastric cancer patients. We are researching to determine the expression of the nine genes in malignant human gastric cancer tissue and to correlate them with clinical information. No significant financial relationships to disclose.
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Patnaik, Mrinal M., and Terra L. Lasho. "Genomics of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes." Hematology 2020, no. 1 (December 4, 2020): 450–59. http://dx.doi.org/10.1182/hematology.2020000130.
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Abstract Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes are uniquely classified neoplasms occurring in both children and adults. This category consists of 5 neoplastic subtypes: chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), BCR-ABL1–negative atypical chronic myeloid leukemia (aCML), MDS/MPN-ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), and MDS/MPN-unclassifiable (U). Cytogenetic abnormalities and somatic copy number variations are uncommon; however, >90% patients harbor gene mutations. Although no single gene mutation is specific to a disease subtype, certain mutational signatures in the context of appropriate clinical and morphological features can be used to establish a diagnosis. In CMML, mutated coexpression of TET2 and SRSF2 results in clonal hematopoiesis skewed toward monocytosis, and the ensuing acquisition of driver mutations including ASXL1, NRAS, and CBL results in overt disease. MDS/MPN-RS-T demonstrates features of SF3B1-mutant MDS with ring sideroblasts (MDS-RS), with the development of thrombocytosis secondary to the acquisition of signaling mutations, most commonly JAK2V617F. JMML, the only pediatric entity, is a bona fide RASopathy, with germline and somatic mutations occurring in the oncogenic RAS pathway giving rise to disease. BCR-ABL1–negative aCML is characterized by dysplastic neutrophilia and is enriched in SETBP1 and ETNK1 mutations, whereas MDS/MPN-U is the least defined and lacks a characteristic mutational signature. Molecular profiling also provides prognostic information, with truncating ASXL1 mutations being universally detrimental and germline CBL mutations in JMML showing spontaneous regression. Sequencing information in certain cases can help identify potential targeted therapies (IDH1, IDH2, and splicing mutations) and should be a mainstay in the diagnosis and management of these neoplasms.
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Yin, C. Cameron, Naveen Pemmaraju, M. James You, Shaoying Li, Jie Xu, Wei Wang, Zhenya Tang, et al. "Integrated Clinical Genotype-Phenotype Characteristics of Blastic Plasmacytoid Dendritic Cell Neoplasm." Cancers 13, no. 23 (November 23, 2021): 5888. http://dx.doi.org/10.3390/cancers13235888.
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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive neoplasm derived from plasmacytoid dendritic cells. While advances in understanding the pathophysiology of the disease have been made, integrated systematic analyses of the spectrum of immunophenotypic and molecular alterations in real-world clinical cases remain limited. We performed mutation profiling of 50 BPDCN cases and assessed our findings in the context of disease immunophenotype, cytogenetics, and clinical characteristics. Patients included 42 men and 8 women, with a median age of 68 years (range, 14–84) at diagnosis. Forty-two (84%) patients had at least one mutation, and 23 (46%) patients had ≥3 mutations. The most common mutations involved TET2 and ASXL1, detected in 28 (56%) and 23 (46%) patients, respectively. Co-existing TET2 and ASXL1 mutations were present in 17 (34%) patients. Other recurrent mutations included ZRSR2 (16%), ETV6 (13%), DNMT3A (10%), NRAS (10%), IKZF1 (9%), SRSF2 (9%), IDH2 (8%), JAK2 (6%), KRAS (4%), NOTCH1 (4%), and TP53 (4%). We also identified mutations that have not been reported previously, including ETNK1, HNRNPK, HRAS, KDM6A, RAD21, SF3A1, and SH2B3. All patients received chemotherapy, and 20 patients additionally received stem cell transplantation. With a median follow-up of 10.5 months (range, 1–71), 21 patients achieved complete remission, 4 had persistent disease, and 24 died. Patients younger than 65 years had longer overall survival compared to those who were ≥65 years (p = 0.0022). Patients who had ≥3 mutations or mutations in the DNA methylation pathway genes had shorter overall survival (p = 0.0119 and p = 0.0126, respectively). Stem cell transplantation significantly prolonged overall survival regardless of mutation status. In conclusion, the majority of patients with BPDCN have somatic mutations involving epigenetic regulators and RNA splicing factors, in addition to ETV6 and IKZF1, which are also frequently mutated. Older age, multiple mutations, and mutations in the DNA methylation pathway are poor prognostic factors.
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Haferlach, Claudia, Anna Stengel, Manja Meggendorfer, Wolfgang Kern, and Torsten Haferlach. "Impact of 1p Deletions in Myelodysplastic Syndromes and Secondary AML Arising from Myelodysplastic Syndromes." Blood 128, no. 22 (December 2, 2016): 2006. http://dx.doi.org/10.1182/blood.v128.22.2006.2006.
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Background: Deletions in the short arm of chromosome 1 are rare, recurrent abnormalities in Myelodysplastic syndromes (MDS) and are observed as the sole abnormality in 0.2% (Schanz et al. JCO 2012). So far no comprehensive characterization of this subset has been performed. Aim: The aim of this study was to characterize MDS and secondary AML evolving from MDS harboring a 1p deletion with respect to 1) accompanying cytogenetic and molecular genetic abnormalities, 2) the size of the 1p deletion and the minimal deleted region. Patients and Methods: 50 cases with MDS (de novo MDS: n=38, t-MDS: n=8) and secondary AML evolving from MDS (n=4) harboring a 1p deletion were selected for analysis. All cases were evaluated by chromosome banding analysis. From 30 cases sufficient material was available to perform genomic array analysis (SurePrint G3 ISCA CGH+SNP Microarray, Agilent, Waldbronn, Germany) and amplicon sequencing to detect mutations in ASXL1, CBL, CSF3R, CSNK1A1, DNMT3A, ETNK1, ETV6, EZH2, GATA1, IDH1, IDH2, JAK, KIT, KRAS, MPL, NPM1, NRAS, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, and U2AF1. Variants of unknown significance were excluded from statistical analysis. Results: 62% were male and median age was 75 years (range: 35 - 91). The 1p deletion was the sole chromosomal abnormality in 5/50 cases (10%) and was accompanied by one, two and more than two additional aberrations in 12 (24%), 15 (30%), and 18 (36%) cases, respectively. In total 129 chromosome abnormalities were observed in addition to the 1p deletion (median per patient: 2, range: 0-9). Of these only 10 were balanced, while 119 were unbalanced abnormalities leading to gain or loss of chromosomal material. Loss of 1p was most frequently accompanied by del(5q) (n=24; 48%), +8 (n=20; 39%), 7q-/-7 (n=11; 22%), del(17p) (n=5; 10%), and -Y (n=3; 6%). In 15 cases (29%) a duplication of the short arm of chromosome 1 harboring the 1p deletion was observed. Genomic array analyses revealed a median size of the 1p deletion of 25 MB (range: 13-34 MB). A minimal deleted region encountered in all 30 evaluable patients ranged from genomic position 17,872,935 to 24,285,861 encompassing 72 genes (e.g. E2F2, ID3, PAX7, UBR4, ZBTB40) and 10 micro RNAs. One, 2, 3, and 4 mutations were present in 10 (33%), 8 (26%), 5 (17%) and 2 (7%) cases, respectively. No mutations in any of the analyzed genes were observed in 5 cases (17%). Mutations were detected in SF3B1 (16%), TET2 (16%), ASXL1 (13%), DNMT3A (13%), EZH2 (13%), NRAS (13%), SRSF2 (13%), TP53 (13%), JAK2 (10%), KRAS (7%), U2AF1 (7%), CALR (3%), IDH2 (3%), MPL (3%), RUNX1 (3%), and SETBP1 (3%). No mutations were detected in CBL, CSF3R, CSNK1A1, ETNK1, ETV6, GATA1, IDH1, KIT, and NPM1. Compared to published data (Bejar et al. NEJM 2012, Papaemmanuil et al. Blood 2013, Haferlach et al. Leukemia 2014) SF3B1 (20-30%) and TET2 (20-30%) mutations seem to be less frequent and mutations in TP53 (6-8%), EZH2 (5-7%), NRAS (4-5%) and KRAS (1-3%) more frequent in MDS with 1p deletion compared to an unselected MDS cohort. Patients harboring either a 1p deletion as the sole abnormality or a duplication of the deleted chromosome 1 (n=20) had an excellent prognosis (3 year overall survival (OS): 100%), while patients with a 1p deletion accompanied by -7/7q- (n=11) had a very poor outcome (3 year OS: 0%; p<0.001). Patients with 1p deletion and other accompanying cytogenetic abnormalities (n=19) had an intermediate outcome (3 year OS: 34%, p=0.03, p=0.003). Conclusions: 1) Interstitial deletions in the short arm of chromosome 1 are rare recurrent abnormalities in MDS. 2) 5q deletion, +8, -7/7q- are frequently observed in addition to 1p deletion. 3) Both MDS with a 1p deletion as the sole abnormality and MDS with a duplication of deleted chromosome 1 are associated with very favorable outcome. 4) Accompanying abnormalities, especially -7/7q- have a negative impact on outcome. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Stengel:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Paikin, Henning. "Psykoanalyse og etik1." Nordisk Psykiatrisk Tidsskrift 42, no. 3 (January 1988): 169–77. http://dx.doi.org/10.3109/08039488809094952.
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Chu, Jian, Xiong-Xian Qian, Xiang-Min Zhang, Ting Jiang, Xiao-Jun Li, and Wei Sun. "ETNK2 Low-Expression Predicts Poor Prognosis in Renal Cell Carcinoma with Immunosuppressive Tumor Microenvironment." Journal of Oncology 2023 (February 21, 2023): 1–11. http://dx.doi.org/10.1155/2023/1743357.
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Background. The ethanolamine kinase 2 (ETNK2) gene is implicated in carcinogenesis, but its expression and involvement in kidney renal clear cell carcinoma (KIRC) remain unknown. Methods. Initially, we conducted a pan-cancer study in which we searched the Gene Expression Profiling Interactive Analysis, the UALCAN, and the Human Protein Atlas databases to determine the expression level of the ETNK2 gene in KIRC. The Kaplan–Meier curve was then used to calculate the overall survival (OS) of KIRC patients. We then used the differentially expressed genes (DEGs) and enrichment analysis to explain the mechanism of the ETNK2 gene. Finally, the immune cell infiltration analysis was performed. Results. Although the ETNK2 gene expression was lower in KIRC tissues, the findings illustrated a link between the ETNK2 gene expression and a shorter OS time for KIRC patients. DEGs and enrichment analysis revealed that the ETNK2 gene in KIRC involved multiple metabolic pathways. Finally, the ETNK2 gene expression has been linked to several immune cell infiltrations. Conclusions. According to the findings, the ETNK2 gene plays a crucial role in tumor growth. It can potentially serve as a negative prognostic biological marker for KIRC by modifying immune infiltrating cells.
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Pieri, Lisa, Giada Rotunno, Francesca Gesullo, Tiziana Fanelli, Giuditta Corbizi Fattori, Annalisa Pacilli, Federica Scarfì, et al. "Prognotic Impact of Mutations in Systemic Mastocytosis." Blood 128, no. 22 (December 2, 2016): 1953. http://dx.doi.org/10.1182/blood.v128.22.1953.1953.
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Abstract Introduction: Systemic mastocytosis (SM) is an heterogeneous myeloproliferative neoplasm characterized by uncontrolled growth of cKIT mutated clonal mast cells, with clinical manifestations ranging from indolent forms (ISM) with only skin lesions and/or anaphylactic shock to smouldering SM (SSM) with evidence of organ involvement to aggressive forms (ASM) with extensive organ damage. SM with an associated hematological neoplasm (SM-AHN) is a subtype with adverse prognosis possibly related to the associated neoplasm rather than SM. Recent data indicate that mutations in genes associated to myeloid malignancies correlate with survival and disease progression but information are still scanty and not completely concordant, and mutations apparently did not correlate with disease manifestations; furthermore, most patients analyzed were SM-AHN, therefore the contribution of mutations associated with the non-mast cell clone could not be ascertained clearly. The aim of this study was to address the prognostic relevance of mutations at diagnosis in a series of 70 pts with SM, excluding SM-AHD. Methods: There were 58 ISM, 4 SSM, 7 ASM and 1 mast cell leukemia (MCL) pts. cKITD816V mutation was assessed by RTQ-PCR. Mutations in myeloid-neoplasm associated genes were assessed by next generation sequencing (NGS) with Ion Torrent PGM platform; analyzed genes included ASXL1, CBL, cKIT, ETNK1, EZH2, IDH1, IDH2, SRSF2, RUNX1, TET2. We also evaluated the cKITD816V variant allele frequency (VAF) by NGS. Kruskal-Wallis test and Chi-squared test were used for analysis of continuous and categorical variables, respectively. Cox regression model was used for survival analysis; variables included were WHO subgroup, cKITD816V >2% VAF, mutations in additional genes, age at diagnosis >60 years, serum tryptase >200 ng/mL, alkaline phosphatase and white blood cells greater than upper normal limit. We did not considered as single entities the features included in B and/or C findings. Results: Median age at diagnosis was 45 years (y)(range 17-76) for ISM, 67 y (53-74) for SSM, 73 (41-81) for ASM (p<0.001). At last follow up (median 2 years, range 0.2-14) 2 pts with ASM evolved to acute myeloid leukemia (AML, 2.8% of all series, 28% of ASM), 1 ISM pts developed organ damage and shifted to ASM; 4 pts died (4/70, 5.7%). Skin involvement was found in 80.6% of pts, 31.3% had history of anaphylaxis and 27.8% osteoporosis. Median serum tryptase levels were 28.7 ng/mL (range 3-192) for ISM, 190 (60-591) for SSM, 64 (23-300) for ASM and 2000 in MCL. All but 3 pts (2 ISM, 1 ASM) were cKITD816V mutated by RT-PCR in bone marrow aspirate (BM) or peripheral blood (PB) (in pts with punctio sicca). 54/67 (80%) had a cKITD816V mutation detectable in PB, underlying that even with high sensitivity methods PB cannot replace BM analysis for diagnosis. Median VAF was 0.34% (range 0.03-38.4) in ISM, 17.2% (0.3-45) in SSM, 26.7% (0.9-81.7) in ASM and 71.7% in MCL. Pts with at least 1 additional mutation were 6.9% (4/54) ISM, 50% (2/4) SSM and 57% (4/7) ASM(p<0.001). Five pts (7%), 4 ASM (57%) and 1 MCL, had more than 1 additional mutations (p<0.001). TET2 was the most frequent mutated gene, in 9/70 cases (12.9%), followed by ASXL1 and SRSF2 in 2 pts (2.9% each) and EZH2, IDH2, CBL and RUNX1 in 1 pts each (1.4%). No mutation was found in IDH1 and ETNK1. No recurrent mutation types were found. All pts with more than one additional mutations other than cKITD816V carried a TET2 mutation combined with ASXL1 and SRSF2 mutation in two cases each and CBL in one case. One pt had a third additional EZH2 mutation. Karyotype was normal in all the 58 pts evaluated, including 5 ASM and 3 SSM. In univariate analysis the following parameters were associated with shorter survival: one or more additional mutations (HR 19.2, CI 2-185, p<0.001), TET2 mutation (HR 28, CI 2.9-271, p=0.004) (mutations in other single genes were not evaluated due to low number of cases) and ASM variant (HR 5.3, CI 1.7-16.1, p=0.003). Pts older than 60 y at diagnosis had higher frequency of additional mutations (35% versus 8% in pts <60 y, p=0.005) and of cKITD816V VAF >2% (68.8% versus 8.3%, P<0.001). None of the analyzed molecular features correlated with anaphylaxis, osteoporosis or skin involvement. Conclusions: With the limitations due the small number of events recorded in this series, these data suggest that knowledge of molecular asset in pts with SM might provide prognostically relevant information. Disclosures Vannucchi: Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau.
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Zhou, Xiyou, Eric T. Weatherford, Xuebo Liu, Ella Born, Henry L. Keen, and Curt D. Sigmund. "Dysregulated human renin expression in transgenic mice carrying truncated genomic constructs: evidence supporting the presence of insulators at the renin locus." American Journal of Physiology-Renal Physiology 295, no. 3 (September 2008): F642—F653. http://dx.doi.org/10.1152/ajprenal.00384.2007.
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We previously generated transgenic mice carrying a large P1 artificial chromosome (PAC160) encompassing a 160-kb segment containing the human renin gene, two upstream genes, and one downstream gene. We also previously generated mutant PAC160 constructs lacking the distal enhancer and concluded it is required to maintain baseline expression of human renin, but is not required for tissue-specific, cell-specific, and regulated expression of renin in vivo. We now report two additional transgenic lines carrying random truncations of PAC160 upstream of the renin gene. Southern and PCR mapping studies indicate that the truncation break points in the two lines are located ∼10.4 and 2.5 kb upstream of the renin gene causing a deletion of all DNA upstream of the break. We tested the hypothesis that large-scale deletion of DNA upstream of the human renin gene including the enhancer would cause dysregulation of human renin expression. Phenotypically, these truncations cause a severe dysregulation of human renin expression, but remarkably, a preservation of the normal tissue-specific expression of the human ethanolamine kinase 2 (ETNK2) gene which lies immediately downstream of renin. Several functional binding sites for CTCF, a mammalian insulator protein, were identified in and around the renin and ETNK2 loci by gel shift and chromatin immunoprecipitation. We conclude that there are sequences in and around the renin and ETNK2 loci which act as boundaries between neighboring genes which insulate them from each other. The study illustrates the value of taking a much wider genomic perspective when studying mechanisms regulating gene expression.
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Maniaci, Breanna, Jooho Chung, Pedro Sanz-Altamira, Daniel J. DeAngelo, and Julia E. Maxson. "A Novel CSF3R Activating Mutation Identified in a Patient with Chronic Neutrophilic Leukemia." Blood 138, Supplement 1 (November 5, 2021): 3582. http://dx.doi.org/10.1182/blood-2021-148100.
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Abstract Mutations in CSF3R, the growth factor receptor that signals to drive neutrophil production, are commonly found in Chronic Neutrophilic Leukemia (CNL). There are two main types of CSF3R mutations in CNL: membrane-proximal point mutations and cytoplasmic truncating mutations. The membrane proximal point mutations-notably T618I-are the most common in CNL. These point mutations lead to the loss of glycosylation sites, causing ligand-independent dimerization of the receptor and enhanced activation of downstream signaling pathways. Previously, these glycan-altering mutations were thought to reside in a relatively restricted region near the membrane spanning 610-618 that contains an N-linked glycosylation site and three putative O-linked glycosylation sites. A 55-year old man presented with a WBC of 50,000 and a predominant neutrophilia with 84% neutrophils and bands and no immature cells. A bone marrow examination showed a markedly hypercellular bone marrow exhibiting myeloid-predominant maturing trilineage hematopoiesis with left-shifted myeloid maturation, mild megakaryocytic atypia (small, hypolobated forms), mild reticulin fibrosis (grade 1 of 3). He had multi-station small volume lymphadenopathy and a spleen that measured 16.6 cm craniocaudally. The findings were most consistent with chronic neutrophilic leukemia. Targeted NGS analysis revealed three mutations in CSF3R: Q739* (VAF 26%), Q741* (VAF 24%) and N579Y (VAF 52%). ASXL1 G646fs (38% VAF) and ETNK1 H243Q (VAF 12%) mutations were also present. The truncating mutations in CSF3R were reported as pathogenic, but the N579Y mutation was listed as a variant of uncertain significance. When truncating mutations occur in CNL, they most frequently occur alongside an activating point mutation. This, combined with the knowledge that N579 was previously mapped as a site of receptor glycosylation prompted us to assess the oncogenicity of this variant. We undertook several parallel approaches to characterize this variant. First, a cytokine independent growth assay was performed in Ba/F3 cells. The CSF3R N579Y variant allowed these cells to proliferate in the absence of cytokine support, similarly to the well characterized CSF3R T618I variant. Furthermore, it enabled growth independent from the ligand for CSF3R (GCSF), indicating that this mutation likely also confers ligand-independent dimerization. In an orthogonal approach, we found that CSF3R N579Y enables primary murine hematopoietic cells to grow in cytokine-free methylcellulose to a similar extent as CSF3R T618I. To understand the downstream consequences of receptor activation we undertook immunoblot analysis and discovered that CSF3R N579Y robustly enhances JAK/STAT and MAPK signaling downstream of the receptor. Because of the know activation of JAK by CSF3R mutations, a JAK1/2 inhibitor (ruxolitinib) has been under investigation for treatment of CSF3R-mutant CNL. We find that CSF3R N579Y confers sensitivity to ruxolitinib in both Ba/F3 cells and murine colony forming unit assays. Furthermore, ruxolitinib inhibited colony formation of CD34 positive cells isolated from a bone marrow aspirate from the patient whose leukemia harbored CSF3R N579Y, CSF3R Q739* and CSF3R Q741* mutations. Collectively, our data suggests that N579Y is a pathogenic and potentially actionable variant and that N-linked glycosylation outside of the membrane-proximal region is necessary to maintain the receptor in an inactive state. Figure 1 Figure 1. Disclosures Sanz-Altamira: Kura Oncology: Consultancy. DeAngelo: Autolus: Consultancy; Forty-Seven: Consultancy; Incyte: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Servier: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Blueprint: Research Funding; Amgen: Consultancy; Agios: Consultancy; Glycomimetrics: Research Funding. Maxson: Ionis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.
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Nanaa, Ahmad, Rama Nana, Zhuoer Xie, Dragan Jevremovic, Phuong L. Nguyen, Cynthia Hengel, Susan M. Geyer, et al. "Predictors of Survival and Time to Progression to Myeloid Neoplasm in Patients with Clonal Cytopenias." Blood 136, Supplement 1 (November 5, 2020): 26–27. http://dx.doi.org/10.1182/blood-2020-142181.
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Background: Clonal cytopenias of Undetermined Significance (CCUS) have a higher risk of progression to myeloid neoplasm (MN) compared to idiopathic cytopenias of undetermined significance (ICUS) (Malcovati et al., Blood, 2017). The implementation of flow cytometric (FC) immune-phenotyping and next generation sequencing (NGS) in clinical practice has improved the diagnosis of these entities but the clinical significance and interaction of these abnormal results are still unknown. In this study we investigated predictive factors that play role in survival and progression to MN in patients with ICUS/CCUS. Methods: Patients (Pts) who had undergone evaluation for unexplained cytopenia and had undergone FC and bone marrow morphological assessment between 3/2015-3/2020 at Mayo Clinic Rochester were included. Pts were excluded if a malignant hematological disorder was diagnosed prior to the time of FC. FC included evaluation of the following parameters: Abnormal expression of HLA-DR/CD13, CD2, CD7, CD45, and CD56 on blasts; and abnormal CD13/CD16 expression and side scatter on granulocytic cells. NGS panel up to 2018 included 34 genes, ASXL1, BCOR, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, GATA1, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, MYD88, NOTCH1, NPM1, NRAS, PHF6, PTPN11, RUNX1, SETBP1, SF3B1, TERT, TET2, TP53, U2AF1, WT1, and ZRSR2; in 2018, BRAF was omitted and 12 genes were added, ANRD26, DDX41, ELANE, ETNK1, KDM6A, MYD88, NOTCH1, RAD21, SH2B3, SRP72, SMC3, and STAG2. Results: Characteristics: Of 490 consecutive pts, 238 (median age 69 years (range 19-92), 66% males) met our inclusion criteria as ICUS. 86 (36%) pts had CCUS (abnormal cytogenetics and/or tested positive for pathogenic mutations on NGS). After a median follow-up of 28 months (95% CI: 20 to 31 months), 21 (25%) patients developed MN and 23 (27%) died during follow-up. Comparing ICUS vs CCUS: upon comparing CCUS pts to ICUS, several factors were found to be significantly different: CCUS pts were older (p= .02); majority male (p= .04), had more abnormal HLA-DR/CD13 (p <.0001), more side-scattered light by FC (p <.0001), more pancytopenia on follow up (p= .02) and more morphologic atypia (<.0001). Overall survival (OS) outcomes in CCUS: Several covariates were significant in univariate models, and model selection was used to generate a risk score based on abnormal CD7, abnormal CD13/CD16, abnormal HLA-DR/CD13, splenomegaly and history of prior chemotherapy or radiotherapy (range: 0 - 4; HR=2.58, [95 CI: 1.69 - 3.94], p<.0001). Risk scores were grouped as low risk (score=0), intermediate risk (score=1), and high risk (score=2+), with estimated 2-yr-OS of 95%, 84%, 40%, respectively (Figure 1). An extended risk score model including NGS factors added ASXL1 and IDH1 mutation status to the previous model (range: 0 - 6; HR=2.72, [95 CI 1.82 - 4.06], p<0.0001). MN-free survival (MNFS) in CCUS: 37 pts either progressed to MN and/or died with a median follow up time for MNFS of 22.4 months. Similar for OS, model selection approaches yielded a composite risk score: splenomegaly, BCOR mutation status, mutation in RAS signaling pathway, abnormal expression of flow markers CD13/CD16, HLA-DR/CD13 or CD7 (HR=3.23, [95 CI: 1.90 - 5.49], p=<0.0001). Risk scores were grouped as low risk (score=0), intermediate risk (score=1), and high risk (score ≥ 2), with estimated 1-yr MNFS of 84%, 74%, and 31%, respectively (Figure 2). Conclusion: CCUS has unique features compared to ICUS. Several factors, including clinical characteristics, immune-phenotyping by FC, and somatic mutations have important impact on risk of progression to MN and on overall survival. Our findings serve as proof-of-concept that such integrated models could help identify CCUS patients at higher risks for progression to MN or death. They can guide treatment accordingly and should be evaluated further. Disclosures Shah: Dren Bio: Consultancy.
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Dulucq, Stephanie, Frédéric Bauduer, Jean-Michel Cayuela, Patrice Chevallier, Pascale Cony-Makhoul, Yannick Le Bris, Laurence Legros, et al. "Onset of Blast Crises in CML Patients in Treatment-Free Remission: Descriptive Analysis of 4 Cases." Blood 138, Supplement 1 (November 5, 2021): 2556. http://dx.doi.org/10.1182/blood-2021-149986.
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Abstract Aims: The onset of blast crisis (BC) in initially chronic phase (CP) CML patients that entered treatment-free remission (TFR) after TKI is an exceptional event, however, there is emerging evidence that this may occur in such patients (pts), although the pathogenesis remains unclear to date. Methods: Anonymous clinical case retrospective data collection from patients' datafiles, after written agreement of living patients, centralisation of available frozen nucleic acid collection from diagnosis and from blast crisis and reanalysis by Next-Generation Sequencing of samples (ASXL1, ASXL2, BCOR, CALR, CBL, CEBP alpha , CSF3R, DNMT3A, EP300, ETNK1, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2 JAK2, KIT, , KRAS,MPL, NPM1, NRAS, PHF6, PTPN11 , RAD2, RUNX1, SETBP1, SF3B1, SH2B3, SMC1A, SMC3, SRSF2, STAG1, STAG2, TET2, TP53, U2AF1, WT1 and ZRSR2 genes analysed) on Illumina platform. CNV analysis were performed using VisCAp or in-house pipelines and/or by Multiplex Ligation Dependant Probe Amplification (MLPA). ABL1 tyrosine kinase domain mutations were screened by NGS on cDNA or directly on DNA. BCR-ABL1 transcripts are expressed in % (IS) with at least 32,000 copies of ABL1 as control. All patients discontinued their TKI after 2 years of MR4.5 and a TKI was resumed in case of MMR loss. Results: Along 15-year experience of TFR in our country and ≥ ~800 patients experiencing a TKI cessation attempt, informations from 4 (~0.5%) TFR CML patients entering BC have been collected. All patients harboured Major BCR transcripts. The chronic phase characteristics are mentioned in Table 1. All these long-lasting CP CML pts were ELTS risk score low, and 1 was harbouring ACA at diagnosis. One pt was mutated for ASXL2 and 2 mutations for EP300, found again at BC. Three pts had IFN-a prior to imatinib for all. Three out of 4 lost their MMR after a first cessation attempt at 12, 10 and 3 months after cessation. Pt #1 experienced a 2 nd cessation attempt 52 months after re-initiation of TKIs and entered lymphoid BC 6 months after a second resumption of TKI for a 2 nd MMR loss. The BC characteristics are mentioned in Table 2. Three out of 4 BC were lymphoid, one had ACA different from those at CP diagnosis. Two pts explored had multiple mutations in Runx1, U2AF1, EP300 and ASXL2 genes, not present at CP diagnosis, in addition to multiple ABL1 mutations in 2 out of 4 pts (2 T315I, 3 P-Loop mutations). All pts underwent chemotherapy + various TKI leading to complete remission (CR) in all and 3 out of 4 pts could be allotransplanted in CR, one relapsed shortly after transplant, and a second one 34 months after transplant. Overall 3 pts are alive with 1 in controlled relapse. Conclusions: The onset of BC after TFR for sustained deep molecular response remains an exceptional event and is probably not induced by this therapeutic procedure. These 4 cases underline the need for a sustained long-lasting molecular follow-up of pts in TFR, although the majority of these BC seem sudden. Figure 1 Figure 1. Disclosures Bauduer: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.
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Kloos, Arnold, Felicitas Thol, Sabrina Klesse, Alessandro Liebich, Arne Trummer, Renate Schottmann, Rubén Trespando Jiménez, et al. "Patient Derived Xenotransplantation Model of Atypical Chronic Myeloid Leukemia (aCML)." Blood 126, no. 23 (December 3, 2015): 2836. http://dx.doi.org/10.1182/blood.v126.23.2836.2836.
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Abstract Background: Atypical chronic myeloid leukemia (aCML) is a rare disorder classified as one of the MPN/MDS overlap syndromes. aCML usually presents like CML but lacks the pathognomonic BCR-ABL fusion found in CML. Most patients progress to acute myeloid leukemia (AML) with a median time to AML of 11.2 months and have a median overall survival of only 12.4 months (Wang et al. Blood 2014). Recurrently mutated genes found in aCML patients include SETBP1 , CSF3R, NRAS, EZH2, ASXL1, ETNK1, and U2AF1. The pathogenesis of aCML is poorly understood and neither specific nor effective treatments besides hematopoietic stem cell transplantation are available. We therefore aimed at developing a patient derived xenotransplantation model that allows serial transplantation and expansion of human leukemic cells and evaluation of novel treatments and drugs in vivo. Patient and Methods: Bone marrow cells were harvested from a patient diagnosed with atypical CML based on persistent leukocytosis, immature circulating myeloid precursors (16% metamyelocytes, 8% myelocytes, 9% blasts), marked dysgranulopoiesis, minimal monocytosis and basophilia, hypercellular bone marrow with high myeloid/erythroid ratio and 6% myeloid blasts, dysplasia in megakaryocytes and erythroid progenitors, and absence of BCR-ABL and mutated JAK2. The patient had moderate anemia and normal platelet counts and cytogenetic analysis showed a normal karyotype. Eight hundred thousand bone marrow cells were injected intravenously in NOD/SCID IL-2 receptor γ (NSG) deficient mice. We monitored these mice for human cell engraftment by regular eye bleeds every 4 weeks. Bone marrow and spleen cells from engrafted mice were retransplanted in secondary and tertiary mice of the NSG strain transgenic for SCF, IL3 and GM-CSF (NSGS). Patient cells were analyzed for mutations in fifty four genes by next generation sequencing and mutations were confirmed by Sanger sequencing in primary patient cells and cells from tertiary mice. Results: Human CD45+ cells from the aCML patient showed increasing engraftment over time in the NSG mouse reaching 16% in peripheral blood and 35% in spleen at 26 weeks after transplantation. In secondary (n=2) and tertiary (n=4) mice we used NSGS recipient mice and observed considerably accelerated engraftment kinetics leading to 19, 21 and 73% human cells in peripheral blood, spleen and bone marrow, respectively, between 12 and 15 weeks after transplantation. The myeloid marker CD33 was expressed in 86% of human bone marrow cells, while lymphoid markers CD3 and CD19 were absent. The stem and progenitor phenotype CD34+CD38- was found in 11% of human cells. The progenitor marker CD123 was expressed in 42% of cells, while the myeloid marker CD14 was expressed in 6% of cells. Hemoglobin levels and platelet counts were considerably lower in secondary and tertiary recipients of aCML cells compared to control animals. Spleens were enlarged at time of sacrifice with an average spleen weight of 150 mg. Morphological evaluation of bone marrow cells in tertiary recipients revealed a characteristic picture for aCML with 39% neutrophils, 8% blasts and 53% myeloid progenitors and monocytes. Molecular analysis identified mutations in ASXL1, RUNX1 and EZH2 with variant allele frequencies of 49, 48 and 46 percent, respectively that were confirmed in human cells from tertiary recipient mice. Thus, we show that primary aCML cells can be expanded and serially transplanted in immunodeficient mice and suggest clonal stability of this model. Conclusion: We provide the first patient derived xenotransplantation model for atypical CML, which preserves the phenotypic and molecular characteristics of the primary disease and allows serial transplantation and expansion of aCML cells. This model will serve to better understand the pathogenesis of aCML and to test urgently needed novel treatment approaches. Disclosures No relevant conflicts of interest to declare.
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Kirschner, Martin MJ, Mirle Schemionek, Matthias Begemann, Susanne Isfort, Kristina Feldberg, Tim H. Brümmendorf, and Steffen Koschmieder. "Elucidation of Additional Mutations By Next-Generation Sequencing Is of Clinical Significance in Patients with Rare MPNs and MDS/MPN Overlap Syndromes." Blood 128, no. 22 (December 2, 2016): 4260. http://dx.doi.org/10.1182/blood.v128.22.4260.4260.
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Abstract Introduction: Recently, next-generation sequencing (NGS) has revolutionized the molecular characterization and understanding of several hematologic entities, including myeloproliferative neoplasms (MPN) and myelodysplastic syndrome (MDS)/MPN overlap syndromes. Nevertheless, the frequency and clinical impact of the mutations detected by NGS, remain largely unclear, especially in rare MPN which were analyzed in this study. Methods: Thus, we established a novel amplicon-based NGS panel, comprising genes that are known to be recurrently mutated in MPN and/or MDS/MPN. Hot spot regions or all exons of the following 32 genes were chosen: ABL, ASXL1, BARD, CALR, CBL, CEBPA, CHEK2, CSF3R, DNMT3A, ETNK1, ETV6, EZH2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NFE2, NRAS, PDGFRA, PTPN11, RUNX1, SETBP1, SF3A1, SF3B1, SH3B2 (LNK), SRSF2, TCF12, TET2, TP53, U2AF1. After establishing this panel, peripheral blood samples of 19 patients, which were diagnosed with CMML(10), aCML(2), MPNu(1), MDS/MPNu or other MPN(6), were analyzed on a MiSeq® illumina sequencer. Variants were only analyzed if the absolute coverage at each SNV site was >50 reads, and the absolute coverage of the mutant allele was 10 or more reads and its relative coverage exceeded 10%. Results: Mean coverage of the run was 1516 reads with good Phred-score quality parameters (>84% of called bases with Q-score >= 30). In 300 bidirectional cycles, a yield of nearly seven gigabases of sequencing data was reached. One out of 19 analyzed patients was excluded from analysis due to insufficient DNA quality. In 89% of the samples(16/18), mutations were detected which had not previously been known to be present in these patients. TET2 (50%, 9/18) and SETBP1 mutations were the most common (44%, 8/18). As expected, TET2 mutations were spread over the entire gene and SETBP1 mutations were restricted to the known hot spot region (exon 4, c.2602-c.2620). Additionally, CSF3R mutations were detected in 22% (4/18) of patients. Epigenetic regulator genes were also affected as EZH2 mutations were detected in 17% (3/18), ASXL1 mutations in 39% (7/18) and IDH1/2 mutations were found in 6% (1/18) of all samples, whereas DNMT3A mutations were not present. Further mutations were found in the following genes: CBL (11%), ETV6 (6%), JAK2V617F (6%), KRAS (11%), NRAS (11%), PTPN11 (6%), SH2B3 (6%) and SRSF2 (11%). Besides previously known mutations, several novel variants could be detected. All but one patient harbored more than one of these mutations. Furthermore, clinical correlates and morphologic and cytogenetic subtypes of each patient were available to associate with the NGS data of individual patients. For example, the one patient with a solitary NRAS c.35G>A (amino acid: p.G12D) mutation showed the most aggressive clinical course in our cohort with transformation to AML only 7 months after first diagnosis of CMML. Moreover, CSF3R mutations have been shown to confer sensitivity to ruxolitinib and may thus open up new avenues of treatment for our patients. Conclusion: In a cohort of unclassified MPN and rare MDS/MPN subtypes, NGS is a powerful tool to characterize samples more extensively. Our data suggests that a more comprehensive understanding of the mutational spectrum may have important clinical impact in individual patients, including diagnosis, prognosis, and more specific treatment. Disclosures Isfort: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; BMS: Honoraria; Mundipharma: Other: Travel; Amgen: Other: Travel; Hexal: Other: Travel. Brümmendorf:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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AOYAMA, Chieko, Akiko OHTANI, and Kozo ISHIDATE. "Expression and characterization of the active molecular forms of choline/ethanolamine kinase-α and -β in mouse tissues, including carbon tetrachloride-induced liver." Biochemical Journal 363, no. 3 (April 24, 2002): 777–84. http://dx.doi.org/10.1042/bj3630777.
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Choline/ethanolamine kinase (ChoK/EtnK) exists as at least three isoforms (α1, α2 and β) in mammalian cells. The physiological significance for the existence of more than one form of the enzyme, however, remains to be determined. In the present study, we examined the expression and distribution of the isoforms in mouse tissues using isoform-specific cDNA probes and polyclonal antibodies raised against each N-terminal peptide sequence. Both Northern- and Western-blot analyses indicated that either the α (α1 plus α2) or the β isoform appeared to be the ubiquitously expressed enzyme. The mRNA abundance for the α isoform was highest in testis, whereas that for the β isoform was relatively high in heart and liver. While the native form of each isoform was reported to consist of either homodimers or homotetramers, our immunotitration studies clearly indicated that a considerable part of the active form of the enzyme consists of α/β hetero-oligomers, with relatively small parts of activity expressed by α/α and β/β homo-oligomers. This is the first experimental evidence for the presence of heteromeric ChoK/EtnK in any source. Thus our results strongly suggested that the activity of ChoK/EtnK in the cell is controlled not only by the level of each isoform but also by their combination to form the active oligomer complex. Carbon tetrachloride (CCl4) was shown to induce ChoK activity 2–4-fold in murine liver. Our analysis for the mechanism involved in this induction revealed that the responsible isoform for CCl4 was α, not β. The level of α mRNA was strongly induced in mouse liver, which resulted in a sustained increase in the amount of the α isoform. Consequently, the composition of α/α homo-oligomers came to represent up to 80% of the total active molecular form of ChoK in CCl4-induced liver, whereas it was less than 20% in normal uninduced liver.
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Zheng, Danni, Lingli Jin, Buran Chen, Yufeng Qi, Adheesh Bhandari, Jialiang Wen, Bangyi Lin, Xiaohua Zhang, and Wei Zhang. "The ETNK2 gene promotes progression of papillary thyroid carcinoma through the HIPPO pathway." Journal of Cancer 13, no. 2 (2022): 508–16. http://dx.doi.org/10.7150/jca.65587.
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Wicks, Ian P., Naras M. Lapsys, Elizabeth Baker, Lynda J. Campbell, Andrew W. Boyd, and Grant R. Sutherland. "Localization of a Human Receptor Tyrosine Kinase (ETK1) to Chromosome Region 3p11.2." Genomics 19, no. 1 (January 1994): 38–41. http://dx.doi.org/10.1006/geno.1994.1009.
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Takahashi, Koichi, Feng Wang, Seth Sahil, Jianhua Zhang, Curtis Gumbs, Ghayas C. Issa, Christopher B. Benton, et al. "Presence of 4 or More Driver Mutations Predicts Poor Response to Hypomethylating Agent (HMA) Therapy and Poor Overall Survival in MDS." Blood 126, no. 23 (December 3, 2015): 1663. http://dx.doi.org/10.1182/blood.v126.23.1663.1663.
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Abstract Background: Recent advance in massively parallel sequencing technology has enabled identification of a number of novel somatic driver mutations in myelodysplastic syndromes (MDS). While these efforts have clearly advanced our understanding of MDS pathogenesis, clinical implication of driver mutations in MDS is less studied. Methods: We performed whole exome sequencing on bone marrow aspiration samples obtained from 114 consecutive patients with untreated MDS. Exome capture was performed using Agilent's SureSelect V4 and sequencing was conducted using Illumina's HighSeq 2000 platform. Sequencing achieved median 124x coverage for the targeted exons. Mutect and Pindel algorithm were used to call single nucleotide variants (SNV) and small indels against virtual common normal reference. Annotation of high-confidence driver mutations followed the previous publication by Pappaemmanuil et al. (Blood 2013). Clonal heterogeneity of driver mutations was assessed in patients who have 2 or more driver mutations by Pearson's goodness of fit test. Results: Among the 114 patients with MDS, total 221 high-confidence driver mutations were detected in 39 genes by sequencing. Eighty eight percent (100/114) of the patients were found to have at least one driver mutation. The number of driver mutation ranged from 1 to 5 per case. Commonly detected driver mutations include TET2 (25%), SRSF2 (22%), ASXL1 (20%), RUNX1 (19%), TP53 (12%), SF3B1 (9%), and U2AF1 (9%). As a rare driver mutation, we confirmed ETNK1 p. N244S mutation in 2 MDS patients (2%). This mutation was recently described as a recurrent somatic mutation in atypical CML (Gambacorti-Passerini et al. Blood 2015). Clonal heterogeneity of driver mutations was evaluable in 65 patients (57%). Nineteen patients were found to have clonal heterogeneity in driver mutations (29%). Among the 114 patients, 61 patients (54%) were treated with HMA therapy. Complete response (CR), partial response (PR), and hematological improvement (HI) was observed in 22 (36%) patients, 4 (7%) patients, and 5 (8%) patients, respectively. Presence of TET2 mutation did not predict response to HMA therapy in this series (P = 0.57) even when we restricted to TET2 mutations with variant allele frequency (VAF) >10%. There was a trend toward poor response to HMA therapy in ASXL1 mutated patients (P = 0.074). None of the other driver mutations were predictive of response to HMA therapy as a sole. However, patients who were found to carry 4 or more driver mutations had significantly poor response to HMA therapy (CR rate 0%) compared to patients with less than 4 driver mutations (P = 0.035). Presence of clonal heterogeneity in driver mutations was not predictive of response to HMA therapy (P = 0.43) In regards to survival outcome, presence of SF3B1 mutation predicted favorable overall survival (OS, P = 0.02) while TP53, and DNMT3A mutations were associated with worse OS (P < 0.001 and P = 0.02, respectively). Presence of clonal heterogeneity in driver mutations was not prognostic for OS (P = 0.71). Patients who were found to have 4 or more driver mutations were associated with significantly worse OS (P = 0.014). None of the patients with 4 or more driver mutations had SF3B1 mutation. Multivariate Cox proportional hazard regression analysis considering dichotomized variables relevant to IPSS-R classification (absolute neutrophil count < 0.8 x 103 / µ l, hemoglobin < 8 g/dL, platelet count < 50 x 103 / µ l, and bone marrow blast > 10%, and poor or very poor risk cytogenetics), SF3B1 mutation, DNMT3A mutation, TP53 mutation, and the number of driver mutations (≥ 4) revealed that the presence of 4 or more driver mutations (HR = 2.72 95% CI: 1.34-5.53, P = 0.06), platelet count < 50 x 103 / µ l (HR = 4.73, 95% CI: 2.53-8.85, P < 0.001), and TP53 mutation (HR = 3.34, 95% CI: 1.65-6.75, P = 0.001) significantly predicted worse OS. Conclusion: With the modern sequencing technology, approximately 90% of MDS patients were found to have at least one known myeloid driver mutation. Presence of 4 or more driver mutations in MDS patients predicted poor response to HMA therapy. Multivariate model incorporating mutation profile showed that the presence of 4 or more driver mutations and TP53 mutation status were significantly prognostic in MDS independent of IPSS-R variables. Screening for driver mutations in MDS has clinical impact and mutation profiles should be incorporated into the existing prognostic model. Disclosures Daver: ImmunoGen: Other: clinical trial, Research Funding. DiNardo:Novartis: Research Funding.
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Martín, Iván, Alicia Serrano, Blanca Navarro, Eva Villamón, Marisa Calabuig, Juan Carlos Hernandez Boluda, Javier F. Chaves, et al. "Impact of Clinical Features, Cytogenetics, Genetic Mutations and Methylation of CDKN2B and DLC-1 Promoters on Treatment Response to Azacitidine." Blood 134, Supplement_1 (November 13, 2019): 5412. http://dx.doi.org/10.1182/blood-2019-129019.
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Introduction : Azacitidine (AZA) is a DNA hypomethylating agent used in myeloid neoplasms, however approximately half of patients show treatment failure or relapse. Last years, several studies have showed that genetic mutations may influence on response and survival of the treated patients. Other biomarkers that have traditionally been associated with the response to AZA are the recovery of the platelet count and the presence of abnormalities in the chromosome 7. Finally, the methylation dynamics of genes promoters could be a useful tool to predict the clinical response. Aim: To assess the predictive value on response to AZA of clinical features, cytogenetics, genetic mutations and the methylation dynamics of CDKN2B and DLC-1 promoters in a series of patients with myeloid neoplasms. Methods: We studied 85 patients with myelodysplastic syndromes (MDS) and 28 patients with acute myeloid leukemia (AML) who received AZA. Treatment schedules included 5-azacytidine 75 mg/m2/day for 7 days (n=62) and 5-azacytidine 75 mg/m2/day for 5 days (n=51). According to the International Working Group (IWG) 2006 criteria for MDS, responders were defined as patients achieving complete remission (CR), bone marrow CR (mCR), partial remission (PR) or stable disease with hematologic improvement (SDHI). Sixteen genes with prior implication in the pathogenesis of myeloid diseases were analyzed: NPM1, FLT3, CEBPA, TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, RUNX1, SETBP1, TP53, SF3B1, SRSF2, U2AF1 and ETNK1. For methylation assay, EZ DNA Methylation-Gold kit (Zymo Research) was employed for the bisulfite treatment of DNA. Methylation of CDKN2B and DLC-1 were qualitatively studied pre- and post-AZA with unmethylated and methylated primers and analysis of the PCR products in a QIAxcel System (Qiagen). Overall survival (OS) was measured from start of AZA treatment until the last follow-up or death from any cause. P values <0.05 were considered as statistically significant. Results: Of the 113 patients analyzed, 46 patients (41%) showed response to AZA (median cycles=6): CR=19, mCR=6, PR=12, and SDHI=9. Stable disease and treatment failure were observed in 20 (17%) and 47 patients (42%), respectively. Analysis of clinical features showed that platelet doubling after the first AZA cycle was significantly associated with a better response (58% vs. 31% responders, P=0.041). Forty-seven patients (42%) had chromosomal abnormalities. A positive co-occurrence between del(7q)/-7 and del(17p) was found (n=6, P<0.001) and was significantly associated with a worse response to AZA (P=0.039). Pre-treatment, genetic mutations were presented in 98 patients (87%) and methylation of CDKN2B and DLC-1 promoters were detected in 50 (44%) and 37 (33%) patients respectively (Figure 1). Patients with SF3B1 mutations showed a better response to AZA (68% vs. 35% responders, P=0.008) and a higher OS (30 vs. 15 months, P=0.019) than the remaining patients. In contrast, patients with mutations in transcription factors (RUNX1, SETBP1, NPM1) showed a worse response to AZA (20% vs. 47% responders, P=0.014) and a lower OS (10 vs. 19 months, P=0.010). Splicing genes mutations (SF3B1, SRSF2 and U2AF1) were related to favourable karyotypes (90% vs. 59%, P<0.001) and a lower DLC-1 methylation (31% vs. 57%, P=0.006). Interestingly, patients with DLC-1 methylation showed higher levels (>5%) of bone marrow blasts (63% vs. 40%, P=0.016), higher frequency of complex karyotypes (40% vs. 15%, P=0.002), a positive co-occurrence with TP53 alterations (38% vs. 16%, P=0.009) and its methylation dynamics showed a strong trend towards predict the response to AZA: 57% of patients without DLC-1 methylation or who reduced it post-treatment responded favourably to the drug and 65% of patients who maintained or increased it did not respond (P=0.053). In addition, leukemia transformation was higher in MDS patients with DLC-1 methylation post-AZA than in the remaining MDS patients (58% vs. 21%, P=0.002). Conclusion: The combination of chromosomal alterations and genetic mutations together with the monitoring of platelet count and DLC-1 methylation could contribute to give light in myeloid neoplasms to the heterogeneity observed both in the response to AZA and in patient survival. Samples and data from patients included in this study were provided by the INCLIVA Biobank (PT13/0010/0004). Disclosures Hernandez Boluda: Incyte: Other: Travel expenses paid.
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Santopietro, Michelina, Giovanna Palumbo, Maria Luisa Moleti, Anna Maria Testi, Luisa Cardarelli, Nicola Monaco, Francesco Malaspina, et al. "Next-Generation Sequencing (NGS) in Childhood Myeloproliferative Diseases (MPD)." Blood 132, Supplement 1 (November 29, 2018): 3049. http://dx.doi.org/10.1182/blood-2018-99-118102.
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Abstract Driver mutations of JAK2, CALR and MPL are found in >90% of adults with BCR-ABL1-negative myeloproliferative neoplasms (MPN). In children, the presence of clonal markers ranges between 22 and 40%, and inherited forms of MPD, such as familial erythrocytosis (FE) and hereditary thrombocytosis (HT), are common. Data on the mutational spectrum and biology of childhood MPD are limited. The aims of this study were: a) to evaluate the ability of a next-generation sequencing (NGS)-based 44-gene analysis to better characterize wild type (WT) MPD, and b) to identify non-canonical and/or non-driver mutations in children and adolescents with MPD. Eighty patients (pts) aged ≤20 years (yrs) at diagnosis of MPD, observed between June 1980 and September 2015, were first investigated with standardized methods for driver mutations of MPN (JAK, MPL, CALR), for genes involved in FE (HRE, EpoR, HIF2α, HIF1α, VHL, PHD1-3, STAT5, LNK, TET2) and HT (THPO, MPL, LNK and TET2). Then, a 44-gene panel providing diagnostic information in myeloid malignancies and in rare inherited erythrocytosis/thrombocytosis (JAK2, CALR, MPL, ASXL1, CBL, C-Kit, CSF3R, CUX1, DNMT3A, ETNK1, EZH2, IDH1, IDH2, IKZF1, KRAS, LNK, NFE2, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, ZRSR2, BPGM, EGLN1 (PHD2), EPAS1 (HIF2A), EPOR, GATA1, GELSOLIN, HBA1, HBA2, HBB, JAK2,MPL, RUNX1, SH2B3, SRC, THPO, VHL, WAS) was employed to better characterize these diseases. Sequencing analyses of DNA from mononuclear peripheral blood cells were performed in 57/80 pts. Eighty pts (M 41, F 39; median age at diagnosis: 149/12 yrs, range 3 months-1911/12 yrs), investigated by standardized methods, were retrospectively classified according to the WHO 2016 criteria as follows: 35 essential thrombocythemia (ET) (10 JAK2V617F, 2 CALR type1, 6 CALR type2, 1 CALR atypical, 16 WT), 9 polycythemia vera (PV) (4 JAK2V617F, 5 WT) and 3 primary myelofibrosis (PMF) (1 JAK2V617F, 2 WT). Twenty-three pts with MPLS505N or MPLV501A mutations and 10 pts with HIF mutations (3 pts) and/or anamnestic criteria of FE (7 WT) were considered HT and FE, respectively. The NGS-based 44-gene panel was applied to 57 MPD pts (11 JAK2V617F, 6 CALR, 12 MPLS505N, 2 MPLV501A, 3 HIF2α and 23 WT). According to the WHO 2016 criteria, 27 pts were ET, 14 HT, 8 FE, 7 PV and 1 PMF. By using the NGS panel, clonal markers were found in 12/23 (52%) pts with MPN WT: HBB and PDH2 in 2 FE, MPLW515_P518>KT in 1 ET pt and non-driver mutations in 9 pts (7 ET, 1 PF and 1 PV). Furthermore, two non-canonical driver mutations, MPLC322G and JAK2G301R were identified in 1 CALR type2 ET and in 1 JAK2V617FPV, respectively. An additional MPLV501M mutation was found in 1 MPLS505N HT. Taken together, among the 57 pts 18 (32%) had one (11/18=68%) or two (7/18=39%) non-driver mutations. Eight of the 34 pts (23.5%) with a clonal marker had additional non-driver mutations, that was single in 6 pts. Within the familial MPD, a single non-driver mutation was found in 3/8 FE pts (37.5%), while no mutations were detected in HT pts. Considering the functional classification of non-driver mutations, we found mutations in signaling (CBL, LNK/SH2B3, CSF3R, KIT, SETBP1) and splicing (U2AF1, ZRSR2) genes in ET and PMF pts, and mutations of epigenetic regulation genes (TET2, ASXL1, DNMT3A) in PV, FE and ET pts (Table 1). The co-occurrence of driver and non-driver mutations in the same individual is illustrated in the circos plot (Figure 1). The use of a NGS-based 44-gene panel in acquired and familial pediatric MPD enabled to identify driver and non-driver mutations, not otherwise detected by conventional methods, with a substantial proportion of MPD pts (81%) showing mutations in the genes analyzed. Interestingly, we found additional neoplastic mutations in some pts with FE. Although the utilized NGS-based panel proved useful to better characterize children and adolescents with MPD, 19% of our pts still remain without any identified clonal marker. Further targeted NGS and whole genome sequencing may enable to better define MPD children without molecular markers. Disclosures Malaspina: Sapienza University, Rome: Other: Resident in Hematology. Foà:ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD.
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Stengel, Anna, Wolfgang Kern, Manja Meggendorfer, Torsten Haferlach, and Claudia Haferlach. "MDS with Deletions in the Long Arm of Chromosome 11 Are Associated with a High Frequency of SF3B1 Mutations." Blood 128, no. 22 (December 2, 2016): 4289. http://dx.doi.org/10.1182/blood.v128.22.4289.4289.
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Background: According to the revised International Prognostic Scoring System (IPSS-R), patients with MDS and deletions in the long arm of chromosome 11 (del(11q)) as sole abnormality are categorized as very good prognosis, even better than patients with a normal karyotype. Molecular data on this rare MDS subset is still limited. Aims: Comprehensive cytogenetic and molecular genetic characterization of MDS patients with del(11q) with and without additional aberrations and evaluation of prognosis. Patient cohorts and methods: Within 9225 unselected cases with de novo MDS, 33 cases with isolated del(11q) (del(11q) sole) and 23 cases with del(11q) accompanied by additional chromosomal aberrations (del(11q) other) were detected. All 56 cases were investigated using chromosome banding analysis (CBA) and interphase FISH. For 46 patients (33 of del(11)q sole, 13 of del(11q) other) material was available for investigation by genomic arrays (SurePrint G3 ISCA CGH+SNP Microarray, Agilent, Waldbronn, Germany). In 44 cases amplicon sequencing was performed to detect mutations in ASXL1, CALR, CBL, CSF3R, CSNK1A1, DNMT3A, ETNK1, ETV6, EZH2, FLT3-TKD GATA1, GATA2, IDH1, IDH2, JAK, KIT, KRAS, MPL, NPM1, NRAS, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and ZRSR2. Variants of unknown significance were excluded from statistical analysis. The cohort comprised 23 male and 33 female patients, median age was 75 years (range: 47-89 years). Results: 33/9925 cases with del(11q) sole were found by CBA (0.4%). In the 23 del(11q) other cases additional aberrations included del(5q) (12/23 cases, 52%), del(20q) (3/23 cases, 13%), del(12p) (2/23 cases, 9%) and +8 (2/23 cases, 9%) as recurrent abnormalities. In 6/23 cases (26%), a complex karyotype (>3 aberrations) was observed. In 13/33 cases with del(11q) sole by CBA, array CGH identified additional chromosomal aberrations (all non-recurrent, submicroscopic). In the total cohort analyzed by array CGH, the size of del(11q) varied between 12 - 58 Mb with a median of 39 Mb. In more detail, in cases with del(11q) sole the size ranged from 12 - 58 Mb (median: 38 Mb), in cases with del(11q) other from 21 - 56 Mb (median: 40 Mb). While the minimal deleted region for cases with del(11q) other was identified between genomic position 107 251 381 - 120 088 150, for cases with del(11q) sole no common minimal deleted region was determined due to the strong variation between the respective deleted regions. Mutation analyses revealed a high frequency of SF3B1 mutations in the total cohort (47%). Mutation frequencies >10% were also detected for ASXL1 (17%), SRSF2 (13%), TET2 (13%) and U2AF1 (10%). The median number of mutations was 1 (range 0-4) without differences between both subgroups. However, the high frequency of SF3B1 mutations was even more prominent when only cases with del(11q) sole were analyzed (56% vs. 23% in del(11q) other). Moreover, mutations in U2AF1 were exclusively found in cases with del(11q) sole (14% vs. 0%). By contrast, mutations in ASXL1 were more frequent in del(11q) other (23% vs. 14%). However, these correlations were not found to be statistically significant due to the low number of cases. Comparison of the SF3B1 mutation loads with the proportion of cells with del(11q) observed by FISH revealed that in most cases, del(11q) is found in the main clone. Ring sideroblasts (≥15%) were detected in 11/45 cases (24%), 10 of them harbored an SF3B1 mutation. The minimal deleted region of del(11q) for SF3B1 mutated cases was identified between 107 789 141 - 119 437 544. In the total cohort, the overall survival (OS) at 5 years was 91% and is thus in line with the very good prognosis as defined by the IPSS-R. A lower OS at 5 years was observed for patients with del(11q) other compared to del(11q) sole, although it was not found to be statistically significant (94% vs. 85%). Conclusion: In 0.4% of MDS patients a del(11q) sole was observed. This incidence is in line with data used for calculation of the IPSS-R (0.7% in Schanz et al., 2012). Especially in cases with del(11q) sole, but also in del(11q) other, a high frequency of SF3B1 mutations was observed, which might explain in part the very good prognosis as stated in the IPSS-R and also observed in the present study. Moreover, these patients were found to show a low number of other molecular mutations. The role of U2AF1 mutations, which were exclusively detected in cases with del(11q) sole, needs further investigation. Disclosures Stengel: MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Julien, Vaidie, Delphine Rea, Sylvain Thepot, Le Pluart Bruno, Nathalie Gachard, Stéphanie Struski, Lydia Roy, et al. "Current Treatments Do Not Improve the Prognosis of Patients with Atypical CML and Unclassified MDS/MPN. a Joint Report from Fi-LMC, FIM, Gfch and GFM." Blood 134, Supplement_1 (November 13, 2019): 2954. http://dx.doi.org/10.1182/blood-2019-127254.
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Background Atypical CML (aCML) is a rare myeloid neoplasm with molecular heterogeneity and overlapping features of MDS and MPN. Distinction from unclassified MDS/MPNu based on WHO criteria remains difficult, and the management of these closely related entities remains ill-codified. Most patients (pts) are managed with cytoreductive agents, but small series have reported responses to hypomethylating agents or tyrosine kinase inhibitors (TKI), notably ruxolitinib. Allogeneic stem cell transplantation (SCT) is considered the only curative option. To instruct clinical trials with novel agents in this rare and heterogeneous population, real-life cohorts must i) provide prognostic factors and molecular characterization able to stratify patients, and ii) benchmark outcomes with current treatment options. Methods The French National observational study of rare MDS/MPNs performed a retrospective analysis of adult patients with MDS/MPN from 35 centers. Cases were centrally reclassified according to the 2016 WHO criteria to exclude CMML, classical MPNs and CNL. All statistical analyses were done without dichotomizing continuous clinical or biological variables. The prognostic influence of treatments was analyzed considering onset of treatment as a time-dependent covariate (Mantel-Byar method). Results The study population included 136 pts (M/F 83/53), with a median age of 72 years. Only 43 (31.6%) met WHO 2016 criteria for aCML while the remaining 93 were classified as MDS/MPNu. At diagnosis, spleen enlargement or other tumor symptoms were present in 36% of pts, while 32% had constitutional symptoms. Mutations in ASXL1, splice genes (U2AF1, SF3B1, SRSF2 or ZRSR2), SETBP1, EZH2, CSF3R, JAK2 and ETNK1 were present in 68.8%, 50.0%, 30.3%, 15.9%, 12.7%, 12.6% and 7.4% of 63 tested cases, respectively. 25 pts had an AML transformation. With a median follow-up of 29.8 months (0.5-276.4) median overall survival (OS) and AML-free survival (AMLFS) were 25.6 and 20.6 months, resp. Median OS was 20.2 versus (vs) 29.7 months in aCML vs MDS/MPNu, resp (log rank test p=0.2) and median AMLFS was 16.6 vs 27.4 months, resp (p=0.09). In univariate analysis, higher WBC (p=0.003) and lower Hb level (p<10-5) predicted significantly shorter OS, while presence of splenomegaly or other tumor symptoms (p=0.08), higher proportion of IMC (p=0.06), lower platelet count (p=0.08) and dyserythropoieisis (p=0.05) tended to shorten OS. Age, gender, presence of constitutional symptoms, bone marrow or peripheral blast percentage or dysmegakaryopoiesis had no significant impact (all p>0.1). Patients with EZH2 mutations had shorter OS (median 9.9 vs 20.6 months in EZH2 wt pts, p=0.03), while other gene mutations had no significant prognostic impact (all p>0.1). All variables with p <0.1 in univariate analyses were included in a multivariate Cox model. After backward selection, only Hb levels (HR= 0.81, p<10-5) and dyserythropoiesis (HR=2.4, p=0.04) retained independent prognostic value. At any time during follow-up, 89 (65.4%) pts received cytoreductive agents (mostly hydroxyurea), while 23 (16.9%) received TKI (ruxolitinib in 12, imatinib in 8, dasatinib in 3 pts) and 18 (13.2%) HMA, resp. Of note, 8/18 pts received HMA at transformation to AML, while all pts received TKIs prior to AML. Finally, 19 pts (14.0%) received an SCT and 35.3% received ≥2 of the above-mentioned types of treatment. Median time to SCT, HMA and TKI were 10.2, 11.9 and 4.7 months, resp. In multivariate Cox models adjusting for baseline Hb level and dyserythropoieisis, neither cytoreduction (p=0.6) nor SCT (p=0.5) were associated with a significant OS improvement. Treatment with HMA was associated with a significantly worse OS (HR=3.0, p=0.001), but this effect was confounded when transformation to AML, as a time-dependent event, was included in the model (HMA: HR= 1.1, p=0.7, AML: HR=5.1, p<10-6). Finally, treatment with TKIs was also associated with significantly worse OS (HR=2.3, p=0.02). This TKI's detrimental effect was confirmed in a model also accounting for baseline WHO, (log-transformed) WBC count, platelet levels and bone marrow blast percentage. Conclusions Anemia and dyserythropoiesis are important prognostic factors in aCML and MDS/MPNu that should be used to stratify pts included in clinical trials. There is currently no standard of care for these overlap syndromes. Treatment with HMAs and TKIs should be restricted to clinical trials. Disclosures Rea: Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Roy:Incyte Biosciences: Consultancy. Caers:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Legros:Novartis: Honoraria; BMS: Honoraria; Incyte Biosciences: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.
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Jin, Yang Oh, Samantha Cheung, Nicholas V. Coleman, and Timothy E. Mattes. "Association of Missense Mutations in Epoxyalkane Coenzyme M Transferase with Adaptation of Mycobacterium sp. Strain JS623 to Growth on Vinyl Chloride." Applied and Environmental Microbiology 76, no. 11 (April 2, 2010): 3413–19. http://dx.doi.org/10.1128/aem.01320-09.
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ABSTRACT Vinyl chloride (VC) is a toxic groundwater pollutant associated with plastic manufacture and chlorinated solvent use. Aerobic bacteria that grow on VC as a carbon and energy source can evolve in the laboratory from bacteria that grow on ethene, but the genetic changes involved are unknown. We investigated VC adaptation in two variants (JS623-E and JS623-T) of the ethene-oxidizing Mycobacterium strain JS623. Missense mutations in the EtnE gene developed at two positions (W243 and R257) in cultures exposed to VC but not in cultures maintained on ethene. Epoxyalkane-coenzyme M transferase (EaCoMT) activities in cell extracts of JS623-E and JS623-T (150 and 645 nmol/min/mg protein, respectively) were higher than that of wild-type JS623 (74 nmol/min/mg protein), and in both variant cultures epoxyethane no longer accumulated during growth on ethene. The heterologous expression of two variant etnE alleles (W243G [etnE1] and R257L [etnE2]) from strain JS623 in Mycobacterium smegmatis showed that they had 42 to 59% higher activities than the wild type. Recombinant JS623 cultures containing mutant EtnE genes cloned in the vector pMV261 adapted to growth on VC more rapidly than the wild-type JS623 strain, with incubation times of 60 days (wild type), 1 day (pMVetnE1), and 35 days (pMVetnE2). The JS623(pMVetnE) culture did not adapt to VC after more than 60 days of incubation. Adaptation to VC in strain JS623 is consistently associated with two particular missense mutations in the etnE gene that lead to higher EaCoMT activity. This is the first report to pinpoint a genetic change associated with the transition from cometabolic to growth-linked VC oxidation in bacteria.
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Fontana, Diletta, Mario Mauri, Rossella Renso, Mattia Docci, Ilaria Crespiatico, Lisa M. Røst, Mi Jang, et al. "ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine." Nature Communications 11, no. 1 (November 23, 2020). http://dx.doi.org/10.1038/s41467-020-19721-w.
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AbstractRecurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. Here, we demonstrate in primary leukemic cells and in cell lines that mutated ETNK1 causes a significant increase in mitochondrial activity, ROS production, and Histone H2AX phosphorylation, ultimately driving the increased accumulation of new mutations. We also show that phosphoethanolamine, the metabolic product of ETNK1, negatively controls mitochondrial activity through a direct competition with succinate at mitochondrial complex II. Hence, reduced intracellular phosphoethanolamine causes mitochondria hyperactivation, ROS production, and DNA damage. Treatment with phosphoethanolamine is able to counteract complex II hyperactivation and to restore a normal phenotype.
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Lou, Jiangyong, Xiaoming Liu, Xiaodong Fan, Xiaoming Xu, Zhichao Wang, and Liqun Wang. "LncRNA FEZF1-AS1 negatively regulates ETNK1 to promote malignant progression of renal cell carcinoma." Journal of Medical Biochemistry, October 13, 2022. http://dx.doi.org/10.5937/jomb0-39710.
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Background: To explore the role of LncFEZF1-AS1 in renal cell carcinoma (RCC) tissues and cells, and the possible molecular mechanism.
Methods: Expressions of LncFEZF1-AS1 in RCC tissues and adjacent ones were detected. The association of LncFEZF1-AS1 level with clinical data of RCC patients was also analyzed. Besides, the differential expressions of LncFEZF1-AS1 in a variety of RCC cell lines were also determined. Then the LncFEZF1-AS1 knockdown model was constructed in RCC cell line to further determine the influences of LncFEZF1-AS1 on the proliferative ability and migration of RCC cells through CCK8 and Transwell experiments. Furthermore, luciferase reporter gene experiment were used to validate the combination of LncFEZF1-AS1 to ETNK1.
Results: Results suggested that expression of LncFEZF1-AS1 was noticeably higher in RCC tumor tissues and the RCC cells. Clinical pathological data analysis also suggested that high LncFEZF1-AS1 expression was in correlation with the pathological stage and the incidence of distant metastasis in RCC patients, and the poor overall survival rate. In vitro experiments demonstrated that knocking down of LncFEZF1-AS1 markedly repressed the proliferation and migration of RCC cell lines. Bioinformatics suggested that LncFEZF1-AS1 can interact with the downstream target gene ETNK1, which was confirmed by the luciferase reporter gene experiments. Western Blot results revealed that knocking down of LncFEZF1-AS1 markedly enhanced ETNK1. qRT-PCR analysis indicated that ETNK1 level was under-expressed in RCC tissues and in negative correlation with LncFEZF1-AS1. Further experiments suggested that knockdown of ETNK1 partially reversed the inhibitory effects of LncFEZF1-AS1 silencing on the proliferative and migrative abilities of RCC cells.
Conclusions: LncFEZF1-AS1 could facilitation the proliferative and migration of RCC cells by regulating the expression of ETNK1. Therefore, FEZF1-AS1 might function as a cancer-promoting factor and possible new therapeutic target for RCC.
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Xing, Ya, Cheng Xu, Xiao Lin, Minmeng Zhao, Daoqing Gong, Long Liu, and Tuoyu Geng. "Complement C3 participates in the development of goose fatty liver potentially by regulating the expression of FASN and ETNK1." Animal Science Journal 92, no. 1 (January 2021). http://dx.doi.org/10.1111/asj.13527.
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Shuai, Wen, Zhuang Zuo, Nianyi Li, Sofia Garces, Fatima Zahra Jelloul, Chi Young Ok, Shaoying Li, et al. "ETNK1 mutation occurs in a wide spectrum of myeloid neoplasms and is not specific for atypical chronic myeloid leukemia." Cancer, December 29, 2022. http://dx.doi.org/10.1002/cncr.34616.
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Zhao, Fang, David S. Bosler, and James R. Cook. "Designing Myeloid Gene Panels." Archives of Pathology & Laboratory Medicine, November 16, 2021. http://dx.doi.org/10.5858/arpa.2021-0124-oa.
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Context.— Next-generation sequencing studies are increasingly used in the evaluation of suspected chronic myeloid neoplasms (CMNs), but there is wide variability among laboratories in the genes analyzed for this purpose. Recently, the Association for Molecular Pathology CMN working group recommended a core 34-gene set as a minimum target list for evaluation of CMNs. This list was recommended based on literature review, and its diagnostic yield in clinical practice is unknown. Objective.— To determine the diagnostic yield of the core 34 genes and assess the potential impact of including selected additional genes. Design.— We retrospectively reviewed 185 patients with known or suspected CMNs tested using a 62-gene next-generation sequencing panel that included all 34 core genes. Results.— The Association for Molecular Pathology's core 34 genes had a diagnostic yield of 158 of 185 (85.4%) to detect at least 1 variant with strong/potential clinical significance and 107 of 185 (57.8%) to detect at least 2 such variants. The 62-gene panel had a diagnostic yield of 160 of 185 (86.5%) and 112 of 185 (60.5%), respectively. Variants of unknown significance were identified in 49 of 185 (26.5%) using the core 34 genes versus 76 of 185 (41.1%) using the 62-gene panel. Conclusions.— This study demonstrates that the Association for Molecular Pathology–recommended core 34-gene set has a high diagnostic yield in CMNs. Inclusion of selected additional genes slightly increases the rate of abnormal results, while also increasing the detection of variants of unknown significance. We recommend inclusion of CUX1, DDX41, ETNK1, RIT1, and SUZ12 in addition to the Association for Molecular Pathology's 34-gene core set for routine evaluation of CMNs.
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Chen, Qian, Chencen Lai, Fa Chen, Yuanting Ding, Yiyuan Zhou, Songbai Su, Ruiqing Ni, and Zhi Tang. "Emodin Protects SH-SY5Y Cells Against Zinc-Induced Synaptic Impairment and Oxidative Stress Through the ERK1/2 Pathway." Frontiers in Pharmacology 13 (February 7, 2022). http://dx.doi.org/10.3389/fphar.2022.821521.
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Zinc is an essential trace element important for the physiological function of the central nervous system. The abnormal accumulation of zinc inside neurons may induce mitochondrial dysfunction and oxidative stress, which contribute to many brain diseases. We hypothesized that natural anthraquinone derivative emodin can protect against neurotoxicity induced by pathological concentrations of zinc via the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and alleviate oxidative stress and mitochondrial dysfunction. Human neuroblastoma (SH-SY5Y 26 cells) was treated with zinc sulfate and different concentrations of emodin, and changes in the levels of ETK1/2 expression, oxidative stress (DCFH-DA staining), mitochondrial function (JC-1 staining), lipid peroxidation (4-hydroxynonenal staining), and DNA oxidation (8-hydroxy-2-deoxyguanosine staining) were examined. Emodin ameliorated zinc-induced altered expression of levels of phosphorylated ERK1/2 (not total ETK1/2) and synaptic proteins (presynaptic SNAP 25, synaptophysin and postsynaptic PSD95) in SH-SY5Y cells. Moreover, emodin inhibited the generation of reactive oxygen species and oxidative stress and facilitated the collapse of mitochondrial membrane potential (ΔΨm) in SH-SY5Y cells. In conclusion, our results indicated that emodin exerts neuroprotective effects against zinc by normalizing synaptic impairment by decreasing the phosphorylation of ERK1/2, reducing reactive oxygen species and protecting mitochondrial function.
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Taniguchi-Ponciano, Keiko, Lesly A. Portocarrero-Ortiz, Gerardo Guinto, Sergio Moreno-Jimenez, Erick Gomez-Apo, Laura Chavez-Macias, Eduardo Peña-Martínez, et al. "The kinome, cyclins and cyclin-dependent kinases of pituitary adenomas, a look into the gene expression profile among tumors from different lineages." BMC Medical Genomics 15, no. 1 (March 8, 2022). http://dx.doi.org/10.1186/s12920-022-01206-y.
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Abstract Background Pituitary adenomas (PA) are the second most common intracranial tumors and are classified according to hormone they produce, and the transcription factors they express. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. Methods Here we performed transcriptome and proteome analysis of tumors derived from POU1F1 (GH-, TSH-, and PRL-tumors, N = 16), NR5A1 (gonadotropes and null cells adenomas, n = 17) and TBX19 (ACTH-tumors, n = 6) lineages as well as from silent ACTH-tumors (n = 3) to determine expression of kinases, cyclins, CDKs and CDK inhibitors. Results The expression profiles of genes encoding kinases were distinctive for each of the three PA lineage: NR5A1-derived tumors showed upregulation of ETNK2 and PIK3C2G and alterations in MAPK, ErbB and RAS signaling, POU1F1-derived adenomas showed upregulation of PIP5K1B and NEK10 and alterations in phosphatidylinositol, insulin and phospholipase D signaling pathways and TBX19-derived adenomas showed upregulation of MERTK and STK17B and alterations in VEGFA-VEGFR, EGF-EGFR and Insulin signaling pathways. In contrast, the expression of the different genes encoding cyclins, CDK and CDK inhibitors among NR5A1-, POU1F1- and TBX19-adenomas showed only subtle differences. CDK9 and CDK18 were upregulated in NR5A1-adenomas, whereas CDK4 and CDK7 were upregulated in POUF1-adenomas. Conclusions The kinome of PA clusters these lesions into three distinct groups according to the transcription factor that drives their terminal differentiation. And these complexes could be harnessed as molecular therapy targets.
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Lesko, Julia, Alexander Triebl, Elvira Stacher-Priehse, Nicole Fink-Neuböck, Jörg Lindenmann, Freyja-Maria Smolle-Jüttner, Harald C. Köfeler, Andelko Hrzenjak, Horst Olschewski, and Katharina Leithner. "Phospholipid dynamics in ex vivo lung cancer and normal lung explants." Experimental & Molecular Medicine, January 6, 2021. http://dx.doi.org/10.1038/s12276-020-00547-x.
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AbstractIn cancer cells, metabolic pathways are reprogrammed to promote cell proliferation and growth. While the rewiring of central biosynthetic pathways is being extensively studied, the dynamics of phospholipids in cancer cells are still poorly understood. In our study, we sought to evaluate de novo biosynthesis of glycerophospholipids (GPLs) in ex vivo lung cancer explants and corresponding normal lung tissue from six patients by utilizing a stable isotopic labeling approach. Incorporation of fully 13C-labeled glucose into the backbone of phosphatidylethanolamine (PE), phosphatidylcholine (PC), and phosphatidylinositol (PI) was analyzed by liquid chromatography/mass spectrometry. Lung cancer tissue showed significantly elevated isotopic enrichment within the glycerol backbone of PE, normalized to its incorporation into PI, compared to that in normal lung tissue; however, the size of the PE pool normalized to the size of the PI pool was smaller in tumor tissue. These findings indicate enhanced PE turnover in lung cancer tissue. Elevated biosynthesis of PE in lung cancer tissue was supported by enhanced expression of the PE biosynthesis genes ETNK2 and EPT1 and decreased expression of the PC and PI biosynthesis genes CHPT1 and CDS2, respectively, in different subtypes of lung cancer in publicly available datasets. Our study demonstrates that incorporation of glucose-derived carbons into the glycerol backbone of GPLs can be monitored to study phospholipid dynamics in tumor explants and shows that PE turnover is elevated in lung cancer tissue compared to normal lung tissue.
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Zhang, Qian, Lei Ding, Tianren Zhou, Qidi Zhai, Chenbo Ni, Chao Liang, and Jie Li. "A metabolic reprogramming-related prognostic risk model for clear cell renal cell carcinoma: From construction to preliminary application." Frontiers in Oncology 12 (September 13, 2022). http://dx.doi.org/10.3389/fonc.2022.982426.
Full textAbstract:
Metabolic reprogramming is one of the characteristics of clear cell renal cell carcinoma (ccRCC). Although some treatments associated with the metabolic reprogramming for ccRCC have been identified, remain still lacking. In this study, we identified the differentially expressed genes (DEGs) associated with clinical traits with a total of 965 samples via DEG analysis and weighted correlation network analysis (WGCNA), screened the prognostic metabolism-related genes, and constructed the risk score prognostic models. We took the intersection of DEGs with significant difference coexpression modules and received two groups of intersection genes that were connected with metabolism via functional enrichment analysis. Then we respectively screened prognostic metabolic-related genes from the genes of the two intersection groups and constructed the risk score prognostic models. Compared with the predicted effect of clinical grade and stage for ccRCC patients, finally, we selected the model constructed with genes of ABAT, ALDH6A1, CHDH, EPHX2, ETNK2, and FBP1. The risk scores of the prognostic model were significantly related to overall survival (OS) and could serve as an independent prognostic factor. The Kaplan-Meier analysis and ROC curves revealed that the model efficiently predicts prognosis in the TCGA-KIRC cohort and the validation cohort. Then we investigated the potential underlying mechanism and sensitive drugs between high- and low-risk groups. The six key genes were significantly linked with worse OS and were downregulated in ccRCC, we confirmed the results in clinical samples. These results demonstrated the efficacy and robustness of the risk score prognostic model, based on the characteristics of metabolic reprogramming in ccRCC, and the key genes used in constructing the model also could develop into targets of molecular therapy for ccRCC.
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Huang, Shuo, Qihan Luo, Junhao Huang, Jiale Wei, Sichen Wang, Chunlan Hong, Ping Qiu, and Changyu Li. "A Cluster of Metabolic-Related Genes Serve as Potential Prognostic Biomarkers for Renal Cell Carcinoma." Frontiers in Genetics 13 (July 7, 2022). http://dx.doi.org/10.3389/fgene.2022.902064.
Full textAbstract:
Renal cell carcinoma (RCC) is the most common type of renal cancer, characterized by the dysregulation of metabolic pathways. RCC is the second highest cause of death among patients with urologic cancers and those with cancer cell metastases have a 5-years survival rate of only 10–15%. Thus, reliable prognostic biomarkers are essential tools to predict RCC patient outcomes. This study identified differentially expressed genes (DEGs) in the gene expression omnibus (GEO) database that are associated with pre-and post-metastases in clear cell renal cell carcinoma (ccRCC) patients and intersected these with metabolism-related genes in the Kyoto encyclopedia of genes and genomes (KEGG) database to identify metabolism-related DEGs (DEMGs). GOplot and ggplot packages for gene ontology (GO) and KEGG pathway enrichment analysis of DEMGs with log (foldchange) (logFC) were used to identify metabolic pathways associated with DEMG. Upregulated risk genes and downregulated protective genes among the DEMGs and seven independent metabolic genes, RRM2, MTHFD2, AGXT2, ALDH6A1, GLDC, HOGA1, and ETNK2, were found using univariate and multivariate Cox regression analysis, intersection, and Lasso-Cox regression analysis to establish a metabolic risk score signature (MRSS). Kaplan-Meier survival curve of Overall Survival (OS) showed that the low-risk group had a significantly better prognosis than the high-risk group in both the training cohort (p < 0.001; HR = 2.73, 95% CI = 1.97–3.79) and the validation cohort (p = 0.001; HR = 2.84, 95% CI = 1.50–5.38). The nomogram combined with multiple clinical information and MRSS was more effective at predicting patient outcomes than a single independent prognostic factor. The impact of metabolism on ccRCC was also assessed, and seven metabolism-related genes were established and validated as biomarkers to predict patient outcomes effectively.