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[PMID]: 26012362
[Au] Autor:Masarova L; Newberry KJ; Pierce SA; Estrov Z; Cortes JE; Kantarjian HM; Verstovsek S
[Ad] Address:Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA....
[Ti] Title:Association of lymphoid malignancies and Philadelphia-chromosome negative myeloproliferative neoplasms: Clinical characteristics, therapy and outcome.
[So] Source:Leuk Res;39(8):822-7, 2015 Aug.
[Is] ISSN:1873-5835
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:The co-occurrence of myeloproliferative and lymphoproliferative neoplasms (MPN/LPN) has been reported, mostly in case reports. The aim of this study was to assess the characteristics and clinical course of the coexistent diseases. Among 9866 patients who presented to our institution from 1960 to 2014, 34 (0.3%) were diagnosed with MPN/LPN. LPN was diagnosed first in 16 patients, second in 15, and at the same time in 3. The time to secondary malignancy was longer when LPN was diagnosed first (119 vs 98 months). Myelofibrosis (41%), polycythemia vera (24%), and essential thrombocythemia (18%) were the most common MPNs, and non-Hodgkin lymphoma (50%) and chronic lymphocytic leukemia (32%) were the most common LPNs. Seventy-three percent of patients treated for MPN and 72% of those treated for LPN achieved a complete response. After a median follow-up from MPN diagnosis of 84 months, 16 patients are alive and 18 died (4 related to MPN and 2 LPN). Coexistent MPN/LPN is a rare event that does not appear to predict worse outcomes. Treatment choice is generally oriented towards controlling the prevalent disease; the other malignancy may influence treatment strategies in selected cases.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1507
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:IM
[St] Status:In-Data-Review

  2 / 1989139 MEDLINE  
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[PMID]: 24883129
[Au] Autor:Nishi M; Kawasaki H; Fujii M; Nagahashi M; Obatake M; Shirai M; Yamamoto K; Harada M
[Ad] Address:Department of General and Digestive Surgery, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime 770-8503 Japan....
[Ti] Title:Middle-preserving pancreatectomy for multifocal intraductal papillary mucinous neoplasms of the pancreas: report of a case.
[So] Source:Clin J Gastroenterol;7:251-4, 2014.
[Is] ISSN:1865-7265
[Cp] Country of publication:Japan
[La] Language:eng
[Ab] Abstract:Multifocal or continuous pancreatic lesion is identified frequently but finding an appropriate surgical approach is quite challenging. Total pancreatectomy is a useful procedure. However, postoperative endocrine and exocrine disturbance is inevitable. Recently, the safety and feasibility of parenchyma preserving pancreatectomy, including middle-preserving pancreatectomy (MPP), have been reported. MPP is a combined procedure of pancreaticoduodenectomy and distal pancreatectomy, while preserving the body of the pancreas, for cases of multifocal pancreatic lesions. So far, there have only been a few reports that have described MPP. We report a case of MPP for multifocal intraductal papillary mucinous neoplasms of the pancreas, describe the surgical procedure, and discuss the feasibility of MPP as parenchyma-preserving pancreatectomy with reference to the literature.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1507
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1007/s12328-014-0472-8

  3 / 1989139 MEDLINE  
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[PMID]: 26175413
[Au] Autor:Meyer SC; Keller MD; Chiu S; Koppikar P; Guryanova OA; Rapaport F; Xu K; Manova K; Pankov D; O'Reilly RJ; Kleppe M; McKenney AS; Shih AH; Shank K; Ahn J; Papalexi E; Spitzer B; Socci N; Viale A; Mandon E; Ebel N; Andraos R; Rubert J; Dammassa E; Romanet V; Dölemeyer A; Zender M; Heinlein M; Rampal R; Weinberg RS; Hoffman R; Sellers WR; Hofmann F; Murakami M; Baffert F; Gaul C; Radimerski T; Levine RL
[Ad] Address:Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA....
[Ti] Title:CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.
[So] Source:Cancer Cell;28(1):15-28, 2015 Jul 13.
[Is] ISSN:1878-3686
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells, murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1507
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:IM
[St] Status:In-Data-Review

  4 / 1989139 MEDLINE  
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[PMID]: 25650089
[Au] Autor:Chen L; Chen W; Mysliwski M; Serio J; Ropa J; Abulwerdi FA; Chan RJ; Patel JP; Tallman MS; Paietta E; Melnick A; Levine RL; Abdel-Wahab O; Nikolovska-Coleska Z; Muntean AG
[Ad] Address:1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA....
[Ti] Title:Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition.
[So] Source:Leukemia;29(6):1290-300, 2015 Jun.
[Is] ISSN:1476-5551
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 data set. We examined the role of mutated Shp2 in leukemias harboring MLL translocations, which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9-mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. Although the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K, suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small-molecule-mediated Mcl1 inhibition, suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1506
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1038/leu.2015.18

  5 / 1989139 MEDLINE  
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[PMID]: 25873175
[Au] Autor:Elkabets M; Pazarentzos E; Juric D; Sheng Q; Pelossof RA; Brook S; Benzaken AO; Rodon J; Morse N; Yan JJ; Liu M; Das R; Chen Y; Tam A; Wang H; Liang J; Gurski JM; Kerr DA; Rosell R; Teixidó C; Huang A; Ghossein RA; Rosen N; Bivona TG; Scaltriti M; Baselga J
[Ad] Address:Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA....
[Ti] Title:AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.
[So] Source:Cancer Cell;27(4):533-46, 2015 Apr 13.
[Is] ISSN:1878-3686
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance, we have observed that SCC cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance.
[Mh] MeSH terms primary: Carcinoma, Squamous Cell/metabolism
Esophageal Neoplasms/metabolism
Head and Neck Neoplasms/metabolism
Proto-Oncogene Proteins/physiology
Receptor Protein-Tyrosine Kinases/physiology
[Mh] MeSH terms secundary: Animals
Antibodies, Monoclonal, Humanized/pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm
Humans
Mice
Phosphatidylinositol 3-Kinases/antagonists & inhibitors
Phosphatidylinositol 3-Kinases/genetics
Phosphatidylinositol 3-Kinases/metabolism
Protein Kinase C/metabolism
Protein Kinase Inhibitors/pharmacology
Proto-Oncogene Proteins/genetics
Proto-Oncogene Proteins/metabolism
Receptor Protein-Tyrosine Kinases/genetics
Receptor Protein-Tyrosine Kinases/metabolism
Signal Transduction
TOR Serine-Threonine Kinases/metabolism
Thiazoles/pharmacology
Xenograft Model Antitumor Assays
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Antibodies, Monoclonal, Humanized); 0 (NVP-BYL719); 0 (Protein Kinase Inhibitors); 0 (Proto-Oncogene Proteins); 0 (Thiazoles); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.137 (PIK3CA protein, human); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (axl receptor tyrosine kinase); EC 2.7.11.13 (Protein Kinase C); PQX0D8J21J (cetuximab)
[Em] Entry month:1506
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:IM
[Da] Date of entry for processing:150415
[St] Status:MEDLINE

  6 / 1989139 MEDLINE  
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[PMID]: 25376967
[Au] Autor:Abdelsattar ZM; Reames BN; Regenbogen SE; Hendren S; Wong SL
[Ad] Address:Department of Surgery, University of Michigan, Ann Arbor, Michigan.
[Ti] Title:Critical evaluation of the scientific content in clinical practice guidelines.
[So] Source:Cancer;121(5):783-9, 2015 Mar 1.
[Is] ISSN:1097-0142
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: Increasing pressures to provide high-quality evidence-based cancer care have driven the rapid proliferation of clinical practice guidelines (CPGs). The quality and validity of CPGs have been questioned, and adherence to guidelines is relatively low. The purpose of this study was to critically evaluate the development process and scientific content of CPGs. METHODS: CPGs addressing management of rectal cancer were evaluated. We quantitatively assessed guideline quality with the validated Appraisal of Guidelines Research & Evaluation (AGREE II) instrument. We identified 21 independent processes of care using the nominal group technique. We then compared the evidence base and scientific agreement for the management recommendations for these processes of care. RESULTS: The quality and content of rectal cancer CPGs varied widely. Mean overall AGREE II scores ranged from 27% to 90%. Across the 5 CPGs, average scores were highest for the clarity of presentation domain (85%; range, 58% to 99%) and lowest for the applicability domain (21%; range, 8% to 56%). Randomized controlled trials represented a small proportion of citations (median, 18%; range, 13%-35%), 78% of the recommendations were based on low- or moderate-quality evidence, and the CPGs only had 11 references in common with the highest-rated CPG. There were conflicting recommendations for 13 of the 21 care processes assessed (62%). CONCLUSIONS: There is significant variation in CPG development processes and scientific content. With conflicting recommendations between CPGs, there is no reliable resource to guide high-quality evidence-based cancer care. The quality and consistency of CPGs are in need of improvement.
[Mh] MeSH terms primary: Evidence-Based Medicine/standards
Practice Guidelines as Topic
Rectal Neoplasms/therapy
[Mh] MeSH terms secundary: Disease Management
Guideline Adherence
Humans
Quality of Health Care
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Em] Entry month:1505
[Cu] Class update date: 150719
[Lr] Last revision date:150719
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:150223
[St] Status:MEDLINE
[do] DOI:10.1002/cncr.29124

  7 / 1989139 MEDLINE  
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[PMID]: 25409150
[Au] Autor:Juric D; Castel P; Griffith M; Griffith OL; Won HH; Ellis H; Ebbesen SH; Ainscough BJ; Ramu A; Iyer G; Shah RH; Huynh T; Mino-Kenudson M; Sgroi D; Isakoff S; Thabet A; Elamine L; Solit DB; Lowe SW; Quadt C; Peters M; Derti A; Schegel R; Huang A; Mardis ER; Berger MF; Baselga J; Scaltriti M
[Ad] Address:Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA....
[Ti] Title:Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor.
[So] Source:Nature;518(7538):240-4, 2015 Feb 12.
[Is] ISSN:1476-4687
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kα) mutation. The patient was treated with the PI(3)Kα inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110ß blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.
[Mh] MeSH terms primary: Breast Neoplasms/drug therapy
Breast Neoplasms/genetics
Drug Resistance, Neoplasm/genetics
PTEN Phosphohydrolase/deficiency
PTEN Phosphohydrolase/genetics
Phosphatidylinositol 3-Kinases/antagonists & inhibitors
Thiazoles/pharmacology
[Mh] MeSH terms secundary: Alleles
Animals
Breast Neoplasms/metabolism
Breast Neoplasms/pathology
Drug Resistance, Neoplasm/drug effects
Female
Humans
Loss of Heterozygosity/drug effects
Loss of Heterozygosity/genetics
Mice
Mice, Nude
PTEN Phosphohydrolase/metabolism
Thiazoles/therapeutic use
Xenograft Model Antitumor Assays
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (NVP-BYL719); 0 (Thiazoles); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (PIK3CA protein, human); EC 2.7.1.137 (PIK3CB protein, human); EC 3.1.3.48 (PTEN protein, human); EC 3.1.3.67 (PTEN Phosphohydrolase)
[Em] Entry month:1502
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:IM
[Da] Date of entry for processing:150212
[St] Status:MEDLINE
[do] DOI:10.1038/nature13948

  8 / 1989139 MEDLINE  
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[PMID]: 25615776
[Au] Autor:Gollub MJ; Lakhman Y; McGinty K; Weiser MR; Sohn M; Zheng J; Shia J
[Ad] Address:1 Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065.
[Ti] Title:Does gadolinium-based contrast material improve diagnostic accuracy of local invasion in rectal cancer MRI? A multireader study.
[So] Source:AJR Am J Roentgenol;204(2):W160-7, 2015 Feb.
[Is] ISSN:1546-3141
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:OBJECTIVE. The purpose of this study was to compare reader accuracy and agreement on rectal MRI with and without gadolinium administration in the detection of T4 rectal cancer. MATERIALS AND METHODS. In this study, two radiologists and one fellow independently interpreted all posttreatment MRI studies for patients with locally advanced or recurrent rectal cancer using unenhanced images alone or combined with contrast-enhanced images, with a minimum interval of 4 weeks. Readers evaluated involvement of surrounding structures on a 5-point scale and were blinded to pathology and disease stage. Sensitivity, specificity, negative predictive value, positive predictive value, and AUC were calculated and kappa statistics were used to describe interreader agreement. RESULTS. Seventy-two patients (38 men and 34 women) with a mean age of 61 years (range, 32-86 years) were evaluated. Fifteen patients had 32 organs invaded. Global AUCs without and with gadolinium administration were 0.79 and 0.77, 0.91 and 0.86, and 0.83 and 0.78 for readers 1, 2, and 3, respectively. AUCs before and after gadolinium administration were similar. Kappa values before and after gadolinium administration for pairs of readers ranged from 0.5 to 0.7. CONCLUSION. On the basis of pathology as a reference standard, the use of gadolinium during rectal MRI did not significantly improve radiologists' agreement or ability to detect T4 disease.
[Mh] MeSH terms primary: Contrast Media
Gadolinium/diagnostic use
Magnetic Resonance Imaging/statistics & numerical data
Rectal Neoplasms/pathology
[Mh] MeSH terms secundary: Adult
Aged
Aged, 80 and over
Female
Humans
Image Enhancement
Male
Middle Aged
Neoplasm Invasiveness
Neoplasm Staging
Observer Variation
Retrospective Studies
[Pt] Publication type:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Contrast Media); AU0V1LM3JT (Gadolinium)
[Em] Entry month:1506
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:150124
[St] Status:MEDLINE
[do] DOI:10.2214/AJR.14.12599

  9 / 1989139 MEDLINE  
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[PMID]: 25271396
[Au] Autor:Lepore SJ; Revenson TA; Roberts KJ; Pranikoff JR; Davey A
[Ad] Address:a Department of Public Health , Temple University , Philadelphia , PA , USA.
[Ti] Title:Randomised controlled trial of expressive writing and quality of life in men and women treated for colon or rectal cancer.
[So] Source:Psychol Health;30(3):284-300, 2015.
[Is] ISSN:1476-8321
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:OBJECTIVE: This randomised trial tested (i) whether a home-based expressive writing (EW) intervention improves quality of life in patients with colorectal cancer (CRC) and (ii) whether the intervention is more beneficial for men or for people who feel constrained in disclosing cancer-related concerns and feelings. DESIGN: Patients treated for CRC were randomised to an EW (n = 101) or control writing (CW; n = 92) group. Assessments were completed at 1 month pre- and post-intervention. Sex and perceived social constraints on disclosure were evaluated as moderators. MAIN OUTCOME MEASURES: Primary outcomes were depressive symptoms, sleep problems and quality of life indicators. RESULTS: Eighty-one per cent of participants completed all writing assignments. Consistent with hypotheses, relative to the CW group, participants in the EW group expressed more negative emotion in writing and rated their writings as more meaningful, personal and emotionally revealing. There were no significant main effects of EW or moderating effects of sex or social constraints on outcomes. CONCLUSIONS: Although EW is feasible to use with persons who have CRC, it was not effective as a stand-alone psychotherapeutic intervention. Neither was it more effective for men nor for people who felt they could not freely disclose cancer-related concerns and feelings.
[Mh] MeSH terms primary: Colonic Neoplasms/psychology
Expressed Emotion
Psychotherapy/methods
Quality of Life
Rectal Neoplasms/psychology
Writing
[Mh] MeSH terms secundary: Aged
Colonic Neoplasms/therapy
Depression
Feasibility Studies
Female
Humans
Male
Middle Aged
Rectal Neoplasms/therapy
Sleep Disorders
Treatment Outcome
[Pt] Publication type:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Em] Entry month:1504
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:IM
[Da] Date of entry for processing:150110
[St] Status:MEDLINE
[do] DOI:10.1080/08870446.2014.971798

  10 / 1989139 MEDLINE  
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[PMID]: 25281607
[Au] Autor:Chen E; Schneider RK; Breyfogle LJ; Rosen EA; Poveromo L; Elf S; Ko A; Brumme K; Levine R; Ebert BL; Mullally A
[Ad] Address:Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;...
[Ti] Title:Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms.
[So] Source:Blood;125(2):327-35, 2015 Jan 8.
[Is] ISSN:1528-0020
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Signaling mutations (eg, JAK2V617F) and mutations in genes involved in epigenetic regulation (eg, TET2) are the most common cooccurring classes of mutations in myeloproliferative neoplasms (MPNs). Clinical correlative studies have demonstrated that TET2 mutations are enriched in more advanced phases of MPNs such as myelofibrosis and leukemic transformation, suggesting that they may cooperate with JAK2V617F to promote disease progression. To dissect the effects of concomitant Jak2V617F expression and Tet2 loss within distinct hematopoietic compartments in vivo, we generated Jak2V617F/Tet2 compound mutant genetic mice. We found that the combination of Jak2V617F expression and Tet2 loss resulted in a more florid MPN phenotype than that seen with either allele alone. Concordant with this, we found that Tet2 deletion conferred a strong functional competitive advantage to Jak2V617F-mutant hematopoietic stem cells (HSCs). Transcriptional profiling revealed that both Jak2V617F expression and Tet2 loss were associated with distinct and nonoverlapping gene expression signatures within the HSC compartment. In aggregate, our findings indicate that Tet2 loss drives clonal dominance in HSCs, and Jak2V617F expression causes expansion of downstream precursor cell populations, resulting in disease progression through combinatorial effects. This work provides insight into the functional consequences of JAK2V617F-TET2 comutation in MPNs, particularly as it pertains to HSCs.
[Mh] MeSH terms primary: DNA-Binding Proteins/genetics
Hematopoietic Stem Cells/pathology
Janus Kinase 2/genetics
Myeloproliferative Disorders/genetics
Proto-Oncogene Proteins/genetics
[Mh] MeSH terms secundary: Animals
Disease Models, Animal
Disease Progression
Flow Cytometry
Gene Expression Profiling
Mice
Mice, Transgenic
Mutation
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (DNA-Binding Proteins); 0 (Proto-Oncogene Proteins); 0 (Tet2 protein, mouse); EC 2.7.10.2 (Jak2 protein, mouse); EC 2.7.10.2 (Janus Kinase 2)
[Em] Entry month:1503
[Cu] Class update date: 150718
[Lr] Last revision date:150718
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:150109
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2014-04-567024


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