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Article ; Online: Early expression of mature αβ TCR in CD4

Laffey, Kimberly G / Stiles, Robert J / Ludescher, Melissa J / Davis, Tessa R / Khwaja, Shariq S / Bram, Richard J / Wettstein, Peter J / Ramachandran, Venkataraman / Parks, Christopher A / Reyes, Edwin E / Ferrer, Alejandro / Canfield, Jenna M / Johnson, Cory E / Hammer, Richard D / Gil, Diana / Schrum, Adam G

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 27, Page(s) e2118529119

Abstract: During normal T cell development in mouse and human, a low-frequency population of immature ... ...

Abstract	During normal T cell development in mouse and human, a low-frequency population of immature CD4
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/metabolism ; Cell Differentiation ; Histocompatibility Antigens/metabolism ; Humans ; Major Histocompatibility Complex ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Receptor, Notch1/genetics ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Antigen, T-Cell, alpha-beta/metabolism ; Thymus Gland/metabolism
Chemical Substances	Histocompatibility Antigens ; Receptor, Notch1 ; Receptors, Antigen, T-Cell ; Receptors, Antigen, T-Cell, alpha-beta
Language	English
Publishing date	2022-06-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2118529119
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Article ; Online: The immune-related microRNA miR-146b is upregulated in glioblastoma recurrence.

Khwaja, Shariq S / Cai, Chunyu / Badiyan, Shahed N / Wang, Xiaowei / Huang, Jiayi

Oncotarget

2018 Volume 9, Issue 49, Page(s) 29036–29046

Abstract: Background: Glioblastoma (GBM) has a high rate of local recurrence despite chemoradiotherapy (CRT). Genome-wide expression profiling was performed on patient tumors before and after chemoradiotherapy to identify genes and gene pathways associated with ... ...

Abstract	Background: Glioblastoma (GBM) has a high rate of local recurrence despite chemoradiotherapy (CRT). Genome-wide expression profiling was performed on patient tumors before and after chemoradiotherapy to identify genes and gene pathways associated with recurrence. Results: Median time to recurrence was 8.9 months with median time to second surgery of 9.6 months. The microRNA (miRNA) analysis identified 9 oncologic and immune-related miRNAs to be differentially expressed, including the hypoxia-related miR-210 and the immune-modulatory miR-146b. More than 1200 differentially-expressed genes were identified with RNA-sequencing (RNA-seq). Gene set enrichment analysis (GSEA) identified p53 signaling, Notch, Wnt, VEGF, and MEK gene sets enriched in recurrent GBM. Consistent with the miRNA profiling data, the miR-146b target gene set from GSEA analysis was also associated with recurrence. Methods: Fourteen patients with GBM recurrence after CRT who had available tumor tissue from the initial diagnosis as well as recurrence were selected. Total RNA was isolated from formalin-fixed paraffin-embedded (FFPE) tumor specimens. Genome-wide expression profiling using RT-PCR for miRNA analysis and RNA-seq for messenger RNA (mRNA) analysis were conducted to identify differentially-expressed genes. GSEA was performed on the differential expression data. Conclusions: Genome-wide expression profiling identifies multiple oncologic and immune-related gene sets associated with GBM recurrence. In particular, immune-related miR-146b is upregulated in recurrence and deserves further investigation.
Language	English
Publishing date	2018-06-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.25528
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Article ; Online: Osteoradionecrosis of the temporal bone: a case series.

Sharon, Jeffrey D / Khwaja, Shariq S / Drescher, Andrew / Gay, Hiram / Chole, Richard A

Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology

2014 Volume 35, Issue 7, Page(s) 1207–1217

Abstract: Objective: To study osteoradionecrosis (ORN) of the temporal bone.: Study design: Retrospective case review.: Setting: Academic medical center.: Patients: Patients were included who had previously undergone radiation to the head and neck and ... ...

Abstract	Objective: To study osteoradionecrosis (ORN) of the temporal bone. Study design: Retrospective case review. Setting: Academic medical center. Patients: Patients were included who had previously undergone radiation to the head and neck and then developed exposed necrotic bone within the ear canal that persisted at least 3 months. Interventions: Patients were treated with a variety of modalities, including conservative therapy with antibiotic ear drops and in-office debridements, hyperbaric oxygen therapy, and surgery. Main outcome measures: To describe the presentation and management of patients with temporal bone osteoradionecrosis. Results: Thirty-three patients with temporal bone osteoradionecrosis were included. The most common site of primary tumor was the parotid gland (n = 11), followed by the nasopharynx (n = 7). The time to development of ORN varied between 1 and 22 years, with mean of 7.9 years. The mean radiation dose was 62.6 Gy to the primary tumor, 53.1 Gy to the affected temporal bone, and 65.2 Gy to the affected tympanic bone. The most common symptoms of ORN were otorrhea (n = 15), hearing loss (n = 13), and otalgia (n = 12). Fifteen patients had bacterial superinfection, most commonly Staphylococcus aureus (n = 9). Conservative therapy was successful at managing symptoms but not in eradicating exposed bone in most patients. Surgery was used for recalcitrant pain, infection, cholesteatoma, cranial neuropathies, and intracranial complications. Conclusion: Osteoradionecrosis is a rare complication of radiation to the temporal bone. Management should be aimed at relief of symptoms, eradication of superinfection, and treatment of other commonly present radiation effects like cholesteatoma and hearing loss.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Debridement ; Ear Canal/pathology ; Ear Canal/surgery ; Female ; Humans ; Hyperbaric Oxygenation ; Male ; Middle Aged ; Osteoradionecrosis/etiology ; Osteoradionecrosis/pathology ; Osteoradionecrosis/surgery ; Parotid Gland/pathology ; Parotid Neoplasms/pathology ; Parotid Neoplasms/radiotherapy ; Radiotherapy/adverse effects ; Retrospective Studies ; Temporal Bone/pathology ; Temporal Bone/surgery ; Treatment Outcome
Language	English
Publishing date	2014-06-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2036790-9
ISSN	1537-4505 ; 1531-7129
ISSN (online)	1537-4505
ISSN	1531-7129
DOI	10.1097/MAO.0000000000000321
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Article ; Online: Prognostic microRNA signatures derived from The Cancer Genome Atlas for head and neck squamous cell carcinomas.

Wong, Nathan / Khwaja, Shariq S / Baker, Callie M / Gay, Hiram A / Thorstad, Wade L / Daly, Mackenzie D / Lewis, James S / Wang, Xiaowei

Cancer medicine

2016 Volume 5, Issue 7, Page(s) 1619–1628

Abstract: Identification of novel prognostic biomarkers typically requires a large dataset which provides sufficient statistical power for discovery research. To this end, we took advantage of the high-throughput data from The Cancer Genome Atlas (TCGA) to ... ...

Abstract	Identification of novel prognostic biomarkers typically requires a large dataset which provides sufficient statistical power for discovery research. To this end, we took advantage of the high-throughput data from The Cancer Genome Atlas (TCGA) to identify a set of prognostic biomarkers in head and neck squamous cell carcinomas (HNSCC) including oropharyngeal squamous cell carcinoma (OPSCC) and other subtypes. In this study, we analyzed miRNA-seq data obtained from TCGA patients to identify prognostic biomarkers for OPSCC. The identified miRNAs were further tested with an independent cohort. miRNA-seq data from TCGA was also analyzed to identify prognostic miRNAs in oral cavity squamous cell carcinoma (OSCC) and laryngeal squamous cell carcinoma (LSCC). Our study identified that miR-193b-3p and miR-455-5p were positively associated with survival, and miR-92a-3p and miR-497-5p were negatively associated with survival in OPSCC. A combined expression signature of these four miRNAs was prognostic of overall survival in OPSCC, and more importantly, this signature was validated in an independent OPSCC cohort. Furthermore, we identified four miRNAs each in OSCC and LSCC that were prognostic of survival, and combined signatures were specific for subtypes of HNSCC. A robust 4-miRNA prognostic signature in OPSCC, as well as prognostic signatures in other subtypes of HNSCC, was developed using sequencing data from TCGA as the primary source. This demonstrates the power of using TCGA as a potential resource to develop prognostic tools for improving individualized patient care.
MeSH term(s)	Biomarkers, Tumor ; Carcinoma, Squamous Cell/diagnosis ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/mortality ; Computational Biology/methods ; Databases, Nucleic Acid ; Female ; Gene Expression Profiling ; Genomics/methods ; Head and Neck Neoplasms/diagnosis ; Head and Neck Neoplasms/genetics ; Head and Neck Neoplasms/mortality ; Humans ; Kaplan-Meier Estimate ; Male ; MicroRNAs/genetics ; Prognosis ; Reproducibility of Results ; Squamous Cell Carcinoma of Head and Neck ; Transcriptome
Chemical Substances	Biomarkers, Tumor ; MicroRNAs
Language	English
Publishing date	2016-04-25
Publishing country	United States
Document type	Journal Article
ISSN	2045-7634
ISSN (online)	2045-7634
DOI	10.1002/cam4.718
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Article ; Online: Metastatic Neoplasm Volume Kinetics Following 2-Stage Stereotactic Radiosurgery.

Damron, Ethan P / Dono, Antonio / Chafi, Hatim / Martir, Magda / Yu, Tse-Kuan / Khwaja, Shariq / Amsbaugh, Mark / Tandon, Nitin / Esquenazi, Yoshua / Blanco, Angel I

World neurosurgery

2022 Volume 161, Page(s) e210–e219

Abstract: Background: Multisession staged stereotactic radiosurgery (SRS) represents an alternative approach for management of large brain metastases (LBMs), with potential advantages over fractionated SRS. This study investigated clinical efficacy and safety of ... ...

Abstract	Background: Multisession staged stereotactic radiosurgery (SRS) represents an alternative approach for management of large brain metastases (LBMs), with potential advantages over fractionated SRS. This study investigated clinical efficacy and safety of 2-stage stereotactic radiosurgery (2-SSRS) in patients with LBMs. Methods: Patients with LBMs treated with 2-SSRS between 2014 and 2020 were evaluated. Demographic, clinical, and radiologic data were obtained. Volumetric measurements at first SRS session, second SRS session, and follow-up imaging studies were obtained. Characteristics that might predict response to 2-SSRS were evaluated through Fisher exact or Mann-Whitney U test. Results: The study included 24 patients with 26 LBMs. Median (range) marginal doses for first and second SRS sessions were 15 Gy (14-18 Gy) and 15 Gy (12-16 Gy), respectively. Median (range) tumor volumes at first SRS session, second SRS session, and 3-month follow-up were 8.1 cm Conclusions: Our study supports the effectiveness and safety of 2-SSRS as a treatment modality for patients with LBMs, especially in poor surgical candidates. The local failure rate and low occurrence of adverse effects are comparable to other staged radiosurgery studies.
MeSH term(s)	Brain Neoplasms/diagnostic imaging ; Brain Neoplasms/radiotherapy ; Brain Neoplasms/surgery ; Humans ; Kinetics ; Neoplasms, Second Primary ; Physics ; Radiosurgery
Language	English
Publishing date	2022-02-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2534351-8
ISSN	1878-8769 ; 1878-8750
ISSN (online)	1878-8769
ISSN	1878-8750
DOI	10.1016/j.wneu.2022.01.109
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Zs.A 1159: Show issues

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Article ; Online: Prognostic factors and survival patterns in pediatric low-grade gliomas over 4 decades.

Youland, Ryan S / Khwaja, Shariq S / Schomas, David A / Keating, Gesina F / Wetjen, Nicholas M / Laack, Nadia N

Journal of pediatric hematology/oncology

2013 Volume 35, Issue 3, Page(s) 197–205

Abstract: Background: This study reports changes in long-term survival after the introduction of modern imaging in pediatric patients with low-grade gliomas (LGGs).: Methods: Records from 351 consecutive pediatric patients diagnosed with LGG between 1970 and ... ...

Abstract	Background: This study reports changes in long-term survival after the introduction of modern imaging in pediatric patients with low-grade gliomas (LGGs). Methods: Records from 351 consecutive pediatric patients diagnosed with LGG between 1970 and 2009 at Mayo Clinic Rochester were reviewed and divided into diagnosis before (group I: 1970 to 1989) and after (group II: 1990 to 2009) postoperative magnetic resonance imaging became regularly used in pediatric LGG. Results: Median progression-free survival (PFS) and overall survival (OS) were not reached. Overall, 10-year PFS was 62% and OS was 90%. On multivariate analysis, improved PFS was associated with gross total resection (GTR; P<0.0001) and postoperative radiation therapy (RT; P<0.0001). In those undergoing less than GTR, PFS was improved with RT, nearing rates of patients receiving GTR (P=0.12). On multivariate analysis, higher OS was associated with GTR (P<0.0001) and pilocytic histology (P=0.03). Group II had fewer headaches, fewer sensory/motor symptoms, less postoperative RT, and more GTRs. OS and PFS were not different between the groups. Conclusions: This large series of pediatric LGG patients with long-term follow-up found no significant changes in OS or PFS over time. Overall, GTR was associated with improved OS and PFS. RT was associated with an improvement in PFS, with the greatest benefit seen in patients undergoing less than GTR.
MeSH term(s)	Adolescent ; Adult ; Brain Neoplasms/mortality ; Brain Neoplasms/pathology ; Child ; Child, Preschool ; Disease Progression ; Female ; Glioma/mortality ; Glioma/pathology ; Humans ; Infant ; Male ; Neoplasm Grading ; Neoplasm Recurrence, Local/mortality ; Neoplasm Recurrence, Local/pathology ; Prognosis ; Survival Rate ; Time Factors ; Young Adult
Language	English
Publishing date	2013-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	1231152-2
ISSN	1536-3678 ; 1077-4114 ; 0192-8562
ISSN (online)	1536-3678
ISSN	1077-4114 ; 0192-8562
DOI	10.1097/MPH.0b013e3182678bf8
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Zs.A 1537: Show issues

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Article ; Online: Quality of Life Outcomes From a Phase 2 Trial of Short-Course Radiation Therapy Followed by FOLFOX Chemotherapy as Preoperative Treatment for Rectal Cancer.

Khwaja, Shariq S / Roy, Amit / Markovina, Stephanie / Dewees, Todd A / Hunt, Steven / Tan, Benjamin / Myerson, Robert J / Olsen, Jeffrey R / Parikh, Parag J

International journal of radiation oncology, biology, physics

2016 Volume 95, Issue 5, Page(s) 1429–1438

Abstract: Purpose: A prospective phase 2 trial of short-course (SC) radiation therapy (RT) with 25 Gy over 5 fractions, followed by 4 cycles of 5-fluorouracil, oxaliplatin, and leucovorin (mFOLFOX6) before surgery was recently completed at our institution. We ... ...

Abstract	Purpose: A prospective phase 2 trial of short-course (SC) radiation therapy (RT) with 25 Gy over 5 fractions, followed by 4 cycles of 5-fluorouracil, oxaliplatin, and leucovorin (mFOLFOX6) before surgery was recently completed at our institution. We present here the patient-reported quality of life (QOL) outcomes from this trial. Methods and materials: Eighty patients with cT3/T4, any N, any M rectal adenocarcinoma planned for resection were enrolled between 2009 and 2012. The QOL data were obtained prospectively using the Functional Assessment of Cancer Therapy-Colon (FACT-C) questionnaire before RT, before surgery, and 1 year after surgery. The previously validated minimally importance difference (MID) method was used to measure clinically significant QOL changes in FACT-C scores for each patient across time points. We examined the role of ostomy on QOL. We also compared QOL with disease outcomes and physician-reported toxicity. Results: The FACT-C questionnaire was completed by 97% of patients before RT, 85% immediately before surgery, and 62% 1 year after surgery. There was no statistically significant change in mean FACT-C scores from before treatment to after treatment. The majority of patients had either no change or an increase in QOL 1 year after treatment using the MID method. There were significant changes in QOL between patients with ostomy versus no ostomy 1 year after treatment for functional well-being (FWB) (14.81 vs 20.52, P=.018) and the colorectal cancer subscale (CCS) using the MID method (P=.004). Patients without ostomy reported stable changes in bowel control 1 year after surgery. There was no statistically significant correlation between QOL and disease recurrence, pathologic complete response, pathologic T stage downstaging, or acute/late toxicity. Conclusions: SC-RT and sequential mFOLFOX6 as preoperative therapy for rectal cancer results in stable patient-reported QOL outcomes 1 year after treatment. These findings in conjunction with previously reported oncologic outcomes support further evaluation of this regimen in a phase 3 setting.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Chemoradiotherapy/psychology ; Combined Modality Therapy/psychology ; Dose Fractionation ; Female ; Fluorouracil/administration & dosage ; Humans ; Leucovorin/administration & dosage ; Male ; Middle Aged ; Organoplatinum Compounds/administration & dosage ; Patient Satisfaction ; Preoperative Care/psychology ; Quality of Life/psychology ; Radiotherapy Dosage ; Rectal Neoplasms/diagnosis ; Rectal Neoplasms/psychology ; Rectal Neoplasms/therapy ; Treatment Outcome
Chemical Substances	Organoplatinum Compounds ; Leucovorin (Q573I9DVLP) ; Fluorouracil (U3P01618RT)
Language	English
Publishing date	2016--01
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article
ZDB-ID	197614-x
ISSN	1879-355X ; 0360-3016
ISSN (online)	1879-355X
ISSN	0360-3016
DOI	10.1016/j.ijrobp.2016.03.020
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Zs.A 1218: Show issues

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Article ; Online: High E6 Gene Expression Predicts for Distant Metastasis and Poor Survival in Patients With HPV-Positive Oropharyngeal Squamous Cell Carcinoma.

Khwaja, Shariq S / Baker, Callie / Haynes, Wesley / Spencer, Christopher R / Gay, Hiram / Thorstad, Wade / Adkins, Douglas R / Nussenbaum, Brian / Chernock, Rebecca D / Lewis, James S / Wang, Xiaowei

International journal of radiation oncology, biology, physics

2016 Volume 95, Issue 4, Page(s) 1132–1141

Abstract: Purpose: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a favorable prognosis. As a result, de-escalation clinical trials are under way. However, approximately 10% of patients will experience distant ...

Abstract	Purpose: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a favorable prognosis. As a result, de-escalation clinical trials are under way. However, approximately 10% of patients will experience distant recurrence even with standard-of-care treatment. Here, we sought to identify novel biomarkers to better risk-stratify HPV-positive patients with OPSCC. Methods and materials: Gene expression profiling by RNA sequencing (RNA-seq) and quantitative polymerase chain reaction was performed on HPV-positive OPSCC primary tumor specimens from patients with and without distant metastasis (DM). Results: RNA-seq analysis of 39 HPV-positive OPSCC specimens revealed that patients with DM had 2-fold higher E6 gene expression levels than did patients without DM (P=.029). This observation was confirmed in a validation cohort comprising 93 patients with HPV-positive OPSCC. The mean normalized E6 expression level in the 17 recurring primary specimens was 13 ± 2 compared with 8 ± 1 in the remaining 76 nonrecurring primaries (P=.001). Receiver operating characteristic analysis established an E6 expression level of 7.3 as a cutoff for worse recurrence-free survival (RFS). Patients from this cohort with high E6 gene expression (E6-high) (n=51, 55%) had more cancer-related deaths (23% vs 2%, P<.001) and DM (26% vs 5%, P<.001) than did patients with low E6 gene expression (E6-low) (n=42, 45%). Kaplan-Meier survival analysis revealed that E6-high had worse RFS (95% vs 69%, P=.004) and cancer-specific survival (97% vs 79%, P=.007). E6-high maintained statistical significance in multivariate regression models balancing surgery, chemotherapy, nodal stage, and smoking status. Gene set enrichment analysis demonstrated that tumors with high E6 expression were associated with P53, epidermal growth factor receptor, activating transcription factor-2, and transforming growth factor-β signaling pathways. Conclusion: High E6 gene expression level identifies HPV-positive OPSCC patients with 5-fold greater risk of distant disease recurrence and worse cancer-specific survival. Validation in a multi-institutional prospective clinical trial is required to assess the utility of E6 gene expression as a clinically useful prognostic biomarker.
MeSH term(s)	Carcinoma, Squamous Cell/mortality ; Carcinoma, Squamous Cell/pathology ; Carcinoma, Squamous Cell/virology ; Female ; Gene Expression Regulation, Viral ; Head and Neck Neoplasms/mortality ; Head and Neck Neoplasms/pathology ; Head and Neck Neoplasms/virology ; Humans ; Male ; Middle Aged ; Neoplasm Metastasis ; Oncogene Proteins, Viral/genetics ; Oropharyngeal Neoplasms/mortality ; Oropharyngeal Neoplasms/pathology ; Oropharyngeal Neoplasms/virology ; Proportional Hazards Models ; Repressor Proteins/genetics ; Sequence Analysis, RNA ; Squamous Cell Carcinoma of Head and Neck
Chemical Substances	E6 protein, Human papillomavirus type 16 ; Oncogene Proteins, Viral ; Repressor Proteins
Language	English
Publishing date	2016-03-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	197614-x
ISSN	1879-355X ; 0360-3016
ISSN (online)	1879-355X
ISSN	0360-3016
DOI	10.1016/j.ijrobp.2016.03.001
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Article: Accelerated partial-breast irradiation: does the evidence stack up?

Shah, Chirag / Badiyan, Shahed / Khwaja, Shariq / Vicini, Frank

Oncology (Williston Park, N.Y.)

2013 Volume 27, Issue 4, Page(s) 344–5, 347

MeSH term(s)	Breast Neoplasms/radiotherapy ; Female ; Humans
Language	English
Publishing date	2013-04
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	1067950-9
ISSN	0890-9091
ISSN	0890-9091
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Zs.A 3168: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: HIV-1 Rev-binding protein accelerates cellular uptake of iron to drive Notch-induced T cell leukemogenesis in mice.

Khwaja, Shariq S / Liu, Hudan / Tong, Caili / Jin, Fang / Pear, Warren S / van Deursen, Jan / Bram, Richard J

The Journal of clinical investigation

2010 Volume 120, Issue 7, Page(s) 2537–2548

Abstract: Somatic activating mutations in Notch1 contribute to the pathogenesis of T cell acute lymphoblastic lymphoma (T-ALL), but how activated Notch1 signaling exerts this oncogenic effect is not completely understood. Here we identify HIV-1 Rev-binding protein ...

Abstract	Somatic activating mutations in Notch1 contribute to the pathogenesis of T cell acute lymphoblastic lymphoma (T-ALL), but how activated Notch1 signaling exerts this oncogenic effect is not completely understood. Here we identify HIV-1 Rev-binding protein (Hrb), a component of the clathrin-mediated endocytosis machinery, as a critical mediator of Notch-induced T-ALL development in mice. Hrb was found to be a direct transcriptional target of Notch1, and Hrb loss reduced the incidence or delayed the onset of T-ALL in mouse models in which activated Notch1 signaling either contributes to or drives leukemogenesis. Consistent with this observation, Hrb supported survival and proliferation of hematopoietic and T cell precursor cells in vitro. We demonstrated that Hrb accelerated the uptake of transferrin, which was required for upregulation of the T cell protooncogene p21. Indeed, iron-deficient mice developed Notch1-induced T-ALL substantially more slowly than control mice, further supporting a critical role for iron uptake during leukemogenesis. Taken together, these results reveal that Hrb is a critical Notch target gene that mediates lymphoblast transformation and disease progression via its ability to satisfy the enhanced demands of transformed lymphoblasts for iron. Further, our data suggest that Hrb may be targeted to improve current treatment or design novel therapies for human T-ALL patients.
MeSH term(s)	Animals ; Cell Differentiation/genetics ; Cells/metabolism ; Clathrin/genetics ; Clathrin/metabolism ; Endocytosis/genetics ; HIV-1/genetics ; HIV-1/metabolism ; Hematopoietic Stem Cells/metabolism ; Humans ; Iron/metabolism ; Leukemia/genetics ; Lymphoma, T-Cell/genetics ; Mice ; Mice, Knockout ; Models, Biological ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; Signal Transduction/genetics ; Signal Transduction/physiology ; T-Lymphocytes/metabolism
Chemical Substances	Clathrin ; Iron (E1UOL152H7)
Language	English
Publishing date	2010-05-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI41277
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In stock of ZB MED Cologne/Königswinter

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More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito