tbuckley/cabot-search huggingface dataset:
Phase I trial of RAD001 (R), bevacizumab (B), and docetaxel (D) for castration-resistant prostate cancer (CRPC)
Authors: M. E. Gross, J. Soscia, S. Sakowsky, O. Castellanos, D. B. Agus
Journal: Journal of Clinical Oncology (2009)

5154 Background: Targeting of mTOR and vascular endothelial growth factor (VEGF) alone or with chemotherapy has been reported for CRPC. We report a dose finding study combining mTOR and VEGF inhibitors along with docetaxel for advanced CRPC. Methods: Eligible patients (pts) had progressive, metastatic, chemo-naive CRPC. A modified adaptive design was used to explore 3 dose levels. 3 pts were treated in each cohort, expanded by 3 pts if a dose limiting toxicity (DLT) was observed. If no DLT occurred after all pts completed 2 cycles in a cohort, pts were enrolled at the next dose level. If a DLT was seen in 2 pts, that dose level was closed. Dose levels included: cohort 1 (D 75 mg/m2, R 2.5 mg, B 15 mg/kg); cohort 2 (D 75 mg/m2, R 5 mg, B 15 mg/kg); and cohort 3 (D 65 mg/m2, R 5 mg, B 15 mg/kg). D+B was given IV day (d) 1 and R PO days 1–21 on a 21 d cycle. Efficacy is explored as: maximal confirmed PSA decline; partial or complete response (PR+CR) by RECIST criteria; and/or changes in bone scintigraphy. Results: 12 patients have been enrolled to complete the dose-finding phase. Baseline median (range) values include: age 70 (58–78) yrs, PSA 115 (4–1336) ng/mL, alkaline phosphatase 107 (37–763) U/L. All pts had PSA elevations, 5 pts had metastasis to lung and/or lymph nodes. 9 pts had bone metastases. Common toxicities were fatigue and mucositis. DLTs by dose level is summarized as: cohort 1, DLT in 1 of 6 pts (neutropenic fever/grade (Gr) 3, pneumonia/Gr 3, 1 individual pt); cohort 2, DLT in 2 of 2 pts (neutropenic fever /Gr 3, 2 pts); cohort 3, DLT in 3 of 4 pts (neutropenic fever /Gr 3 and Gr 5, pulmonary embolism/ Gr 3, 3 pts). A pt in cohort 3 died from neutropenic fever and sepsis at cycle 3 despite dose modifications and growth factor support. Preliminary measures of efficacy by method of assessment and cohort assignment are summarized ( Table ). Conclusions: We conclude that the cohort 1 dose level of D 75 mg/m2, R 2.5 mg, B 15 mg/kg is safe and demonstrates anti-cancer efficacy. Pt accrual continues at this dose level for the dose-expansion phase of the study. [Table: see text] No significant financial relationships to disclose.
DUO: A phase 3 trial of the PI3K-δ,γ inhibitor IPI-145 versusofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.
Authors: Ian Flinn, Ulrich Jäger, Fritz Offner, Florence Cymbalista, Michael Hallek, Federico Caligaris-Cappio, Julio Delgado, Peter Hillmen, Matthew Steven Davids, David Donald Wright, James H. Essell, Bartrum W Baker, Walter Cosolo, Patrick Francis Kelly, Patricia Harris, Lixin Han, Fiona Patterson, Stephan Stilgenbauer
Journal: Journal of Clinical Oncology (2014)

TPS7122 Background: Phosphoinositide 3-kinase (PI3K)-δ,γ isoforms are preferentially expressed in leukocytes and are central to the growth and survival of certain B and T cell malignancies. Inhibition of these isoforms by IPI-145, an oral PI3K-δ,γ inhibitor, has unique therapeutic potential in hematologic malignancies. IPI-145 has shown clinical activity and a favorable safety profile in a broad range of hematologic malignancies in an ongoing phase 1 trial (IPI-145-02). Based on these data, the DUO phase 3 trial (IPI-145-07; ClinicalTrials.gov number: NCT02004522) has been initiated to evaluate the efficacy and safety of IPI-145 compared to ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Methods: This open-label, two-arm trial includes adult patients with active CLL/SLL who meet at least one of the International Workshop on CLL (IWCLL) 2008 treatment criteria; have disease progression during or after previous CLL therapy; are not appropriate for purine analog-based therapy; and not refractory to ofatumumab. The trial will enroll approximately 300 patients, randomized 1:1 to IPI-145 or ofatumumab at sites in and outside the US. Patients randomized to IPI-145 will receive 25 mg IPI-145 orally, twice daily in 28-day treatment cycles for up to 18 cycles or until disease progression or unacceptable toxicity. After 18 cycles, patients may receive additional cycles of IPI-145 for up to 3 years, if they have documented evidence of response and disease requiring continued treatment. Patients randomized to ofatumumab will receive treatment consistent with the approved product label. Patients on both arms will be followed for up to 3 years from the first dose of study drug. The primary efficacy endpoint is progression-free survival. Key secondary endpoints include safety, overall survival and pharmacokinetic parameters. Patients with progressive disease during the trial may be eligible to receive the opposite study medication in a separate Infinity-sponsored extension protocol (IPI-145-12). This trial is currently enrolling patients. Clinical trial information: NCT02004522.
Ten Year-Old Male with Hemoglobin Lufkin/Beta-Zero Thalassemia Compound Heterozygote Who Exhibited Beta-Thalassemia Major Characteristics.
Authors: Ahna M. Blutreich, Peihong Shu, Jeremy S. Bragdon, Paul J. Kurtin, James D. Hoyer, Gungor Karayalcin
Journal: Blood (2005)
Complementary Diagnostic and Prognostic Value of Parallel Karyotyping and Molecular Diagnostics in Patients with Acute Leukemias.
Authors: Anna Ejduk, Miroslaw Majewski, Iwona Solarska, Hanna Makuch-Lasica, Iwona Kania, Grazyna Nowak, Ilona Seferynska, Lech Konopka, Krzysztof Warzocha
Journal: Blood (2005)
Development of BAX 826, a Polysialylated Full-Length rFVIII with Significantly Improved PK Properties
Authors: Peter L. Turecek, Juergen Siekmann, Artur Mitterer, Michael Graninger, Gerald Schrenk, Peter Matthiessen, Hanspeter Rottensteiner, Werner Hoellriegl, Marietta Putz, Hans Peter Schwarz, Friedrich Scheiflinger
Journal: Blood (2015)
The Genotypic Combination of Homozygous Carriers of Both H1 Haplotype and 34C Shows a Significantly Lower Responsiveness to ADP-Induced Platelet Aggregation Than Others in Healthy Volunteers.
Authors: Koji Isobe, Yumiko Matsubara, Shinichi Takahashi, Miho Iwashita, Risa Komine, Aya Shimizu, Toshihiro Uchida, Hiroaki Ishihara, Toshiro Shibano, Gentaro Watanabe, Yasuo Ikeda, Mitsuru Murata
Journal: Blood (2005)
Особливості показників рН-моніторингу у хворих на ГЕРХ при поєднанні з дисфункцією сфінктера Одді
Authors: Yu.M. Stepanov, I.V. Kushnirenko, L.N. Mosiychuk, L.V. Demeshkina, O.P. Petishko
Journal: GASTROENTEROLOGY (2020)

Стаття присвячена результатам вивчення поєднаного перебігу захворювань верхнього відділу шлунково-кишкового тракту — гастроезофагеальної рефлюксної хвороби та дисфункції сфінктера Одді. У результаті проведеного дослідження показано, що показники рН-моніторингу в дистальному відділі стравоходу прямо пов’язані з наявністю клінічних проявів, характерних для гастроезофагеальної рефлюксної хвороби. Також доведено, що зміни тонусу сфінктера Одді, незалежно від їх характеру, негативно впливають на перебіг гастроезофагеальної рефлюксної хвороби, обтяжуючи його.
Erratum: Corrigendum: WNK1 kinase balances T cell adhesion versus migration in vivo
Authors: Robert Köchl, Flavian Thelen, Lesley Vanes, Tiago F Brazão, Kathryn Fountain, Jian Xie, Chou-Long Huang, Ruth Lyck, Jens V Stein, Victor L J Tybulewicz
Journal: Nature Immunology (2017)
Genome-Wide Analysis of Genetic Alterations in Chronic Myelogenous Leukemia.
Authors: Charles G Mullighan, Ina Radtke, Jinghui Zhang, Letha A. Phillips, Xiaoping Su, Jing Ma, Zhongling Cai, Timothy P. Hughes, Deborah L White, Andrew W. Roberts, Lynda J. Campbell, Sheila A. Shurtleff, James R. Downing
Journal: Blood (2008)
Retention of Slow-Cycling CD34+ cells During Imatinib Treatment and Rapid Decline After 2nd ABL-TKI Treatment in Ph+ Leukemia Cells
Authors: Yosuke Minami, Akihiro Abe, Miho Minami, Yachiyo Kuwatsuka, Nobuaki Fukushima, Kunio Kitamura, Junji Hiraga, Kazuhito Yamamoto, Catriona Jamieson, Tomoki Naoe
Journal: Blood (2011)
Thrombocytosis over 800 × 109/L Following the Use of Pegfilgrastim after Chemotherapy R-MegaCHOP in Patients with Diffuse Large B-Cell Lymphoma.
Authors: Petr Lemez, Milada Jankovska, Robert Pytlik, Hana Subrtova, Jindrich Polivka, Ludmila Novakova, Tomas Kozak
Journal: Blood (2006)
Final Results of the First Randomized Trial Comparing Balloon Kyphoplasty (BKP) to Non-Surgical Management Among Cancer Patients with Vertebral Compression Fractures: Marked Improvement in Back Function, Quality of Life and Pain in the BKP Arm.
Authors: James R Berenson, Robert Pflugmacher, Peter Jarzem, Jeffrey A Zonder, John B Tillman, Talat Ashraf, Frank D Vrionis
Journal: Blood (2009)
Novel View on Stem Cell Compartment and Aging - a Number of Pluripotent Very Small Embryonic Like Stem Cells and Hematopoietic Stem Cells in Murine Bone Marrow Is High in Several Long-Living and Reduced in Short-Living Murine Strains and Unexpectedly Inversely Correlates in These Animals with Plasma Growth Hormone/Insulin-Like Growth Factor-1 Level
Authors: Magda Kucia, Janina Ratajczak, Rui Liu, Dong-Myung Shin, Michal Masternak, Andrzej Bartke, Mariusz Z Ratajczak
Journal: Blood (2011)
Intensive Chemotherapy of 107 Primary Mediastinal B-Cell Lymphoma Patients. Single Center Experience
Authors: Jana Konstantinovna Mangasarova, Sergey Kirillovich Kravchenko, Aminat Umaraskhabovna Magomedova, Anna Misyurina, Elena Baryakh, Vladimir Ivanovich Vorobiev, Eduard G. Gemdzhian, Ekaterina Nesterova, Alisa Igorevna Gilenko, Liliya Gorenkova, Ekaterina Penskaya, Oleg Victorovich Margolin, Valeri Savchenko
Journal: Blood (2015)
NOTCH1 Induces Differential Epigenomic Patterning and Genomic Organization in Fetal Liver- and Adult Bone Marrow-Derived Hematopoietic Progentiors
Authors: Vincenzo Giambra, Sonya H Lam, Miriam Belmonte, Sam Gusscott, Sohrab Salehi, Fong Chun Chan, Robert Kridel, Alireza Lorzadeh, Catherine Hoofd, Christian Steidl, Connie J. Eaves, Martin Hirst, Andrew P. Weng
Journal: Blood (2015)
The Efficacy of H. pylori Eradication Therapy in H. pylori-Infected and Uninfected Patients with Immune Thrombocytopenic Purpura: A Systematic Review.
Authors: Donald M. Arnold, Ashley Bernotas, Ishac Nazi, Roberto Stasi, Masataka Kuwana, John G. Kelton, Mark A. Crowther
Journal: Blood (2008)
Growth faltering in rural Gambian children after four decades of interventions: a retrospective cohort study
Authors: Helen M Nabwera, Anthony J Fulford, Sophie E Moore, Andrew M Prentice
Journal: The Lancet Global Health (2017)

Growth faltering remains common in children in sub-Saharan Africa and is associated with substantial morbidity and mortality. Due to a very slow decline in the prevalence of stunting, the total number of children with stunting continues to rise in sub-Saharan Africa. Identification of effective interventions remains a challenge.We analysed the effect of 36 years of intensive health interventions on growth in infants and young children from three rural Gambian villages. Routine growth data from birth to age 2 years were available for 3659 children between 1976 and 2012. Z scores for weight-for-age, length-for-age, weight-for-length, mid-upper-arm circumference, and head circumference were calculated using the WHO 2006 growth standards. Seasonal patterns of mean Z scores were obtained by Fourier regression. We additionally defined growth faltering as fall in Z score between 3 months and 21 months of age.We noted secular improvements in all postnatal growth parameters (except weight-for-length), accompanied by declines over time in seasonal variability. The proportion of children with underweight or stunting at 2 years of age halved during four decades of the study period, from 38·7% (95% CI 33·5-44·0) for underweight and 57·1% (51·9-62·4) for stunting. However, despite unprecedented levels of intervention, postnatal growth faltering persisted, leading to poor nutritional status at 24 months (length-for-age Z score -1·36, 95% CI -1·44 to -1·27, weight-for-age Z score -1·20, -1·28 to -1·11, and head circumference Z score -0·51, -0·59 to -0·43). The prevalence of stunting and underweight remained unacceptably high (30·0%, 95% CI 27·0-33·0, for stunting and 22·1%, 19·4 to 24·8, for underweight).A combination of nutrition-sensitive and nutrition-specific interventions has achieved a halving of undernutrition rates, but despite these intensive interventions substantial growth faltering remains. We need to understand the missing contributors to growth faltering to guide development of new interventions.UK Medical Research Council, UK Department for International Development.
Use of Plasma RNA for Real-Time Quantitative RT-PCR to Monitor Imatinib Therapy in Patients with Chronic Myeloid Leukemia.
Authors: Vilmos A. Thomazy, Hagop M. Kantarjian, Maha Imam, Peter J. Davies, Christine Aguilar, Iman Jilani, Jorge Cortes, Francis J. Giles, Maher Albitar
Journal: Blood (2004)
There’s more to Obamacare than health insurance
Authors: Douglas Kamerow
Journal: BMJ (2017)

Will public health, research, and quality improvement funding be repealed as well?



As Donald J Trump takes the oath of office to be the 45th US president, Congress has already begun the process of repealing the Affordable Care Act (“Obamacare”). Despite having a majority in both houses of Congress, Republicans cannot simply repeal the Act, because they don’t have the “super-majority” of the Senate that would be needed to cut off a Democratic filibuster. They can, however, by invoking an arcane and complex legislative process called “budget reconciliation,” limit debate on laws and pass them with their simple majority. This is the process they have just begun by passing budget …
Analysis of Molecular Data and the Emergence of Mutations for Chronic-Phase Chronic Myelogenous Leukemia (CML-CP) Patients Treated with Dasatinib After Imatinib Failure.
Authors: Susan Branford, Andreas Hochhaus, Martin Mueller, Erkut Bahceci, Lynn Ploughman, Jaydip Mukhopadhyay, Timothy Hughes
Journal: Blood (2009)
PTCH1 Expression At Diagnosis Reliably Predicts Treatment Failure in Imatinib-Treated Chronic Myeloid Leukaemia Patients
Authors: Juan M. Alonso-Dominguez, Jacob Grinfeld, Mary Alikian, David Marin, Alistair Reid, Mustafa Daghistani, Jane Apperley, John M Goldman, Corinne Hedgley, Steve O‘Brien, Richard E. Clark, Letizia Foroni, Gareth Gerrard
Journal: Blood (2012)
Recovery of KIR Expression After Allogeneic Stem Cell Transplantation in Multiple Myeloma Patients
Authors: Thomas Stuebig, Michael Lioznov, Ulrike Fritsche-Friedland, Haefaa Alchalby, Christine Wolschke, Francis Ayuk, Ulrike Bacher, Axel R. Zander, Nikolaus Kroeger
Journal: Blood (2011)
Gene expression profiling in childhood acute leukaemia; a useful classification tool and a first promising insight into drug resistance.
Authors: Frederik W. Van Delft, Tony Bellotti, L. K. Jones, Naina Patel, Mark Skinner, M. Hubank, I Hann, D. Fletcher, Jean Sargent, Colin Taylor, A Gammerman, Vaskar Saha
Journal: Blood (2003)
Gaze-Contingent Music Reward Therapy for Social Anxiety Disorder: A Randomized Controlled Trial
Authors: Amit Lazarov, Daniel S. Pine, Yair Bar-Haim
Journal: American Journal of Psychiatry (2017)

Objective: Patients with social anxiety disorder exhibit increased attentional dwelling on social threats, providing a viable target for therapeutics. This randomized controlled trial examined the efficacy of a novel gaze-contingent music reward therapy for social anxiety disorder designed to reduce attention dwelling on threats. Method: Forty patients with social anxiety disorder were randomly assigned to eight sessions of either gaze-contingent music reward therapy, designed to divert patients' gaze toward neutral stimuli rather than threat stimuli, or to a control condition. Clinician and self-report measures of social anxiety were acquired pretreatment, posttreatment, and at 3-month follow-up. Dwell time on socially threatening faces was assessed during the training sessions and at pre- and posttreatment. Results: Gaze-contingent music reward therapy yielded greater reductions of symptoms of social anxiety disorder than the control condition on both clinician-rated and self-reported measures. Therapeutic effects were maintained at follow-up. Gaze-contingent music reward therapy, but not the control condition, also reduced dwell time on threat, which partially mediated clinical effects. Finally, gaze-contingent music reward therapy, but not the control condition, also altered dwell time on socially threatening faces not used in training, reflecting near-transfer training generalization. Conclusions: This is the first randomized controlled trial to examine a gaze-contingent intervention in social anxiety disorder. The results demonstrate target engagement and clinical effects. This study sets the stage for larger randomized controlled trials and testing in other emotional disorders.
IMiD® Immunomodulatory Agents Promote Apoptosis in Multiple Myeloma Cells through Induction of TRAIL Expression
Authors: Michael D. Amatangelo, Chad C. Bjorklund, Anita K. Gandhi, Anke Klippel, Tom Daniel, Rajesh Chopra, Matthew Trotter, Anjan Thakurta
Journal: Blood (2015)
The CXCR4/SDF-1 Axis Regulates Migration and Adhesion in Waldenstrom Macroglobulinemia.
Authors: Hai Ngo, Evdoxia Hatjiharissi, Xavier Leleu, Judith Runnels, Anne-Sophie Moreau, Xiaoying Jia, Garrett O’Sullivan, Daniel Santos, Lian Xu, Steven Treon, Teru Hideshima, Kenneth Anderson, Irene Ghobrial
Journal: Blood (2006)
Improved Survival for 149 First-Line Multiple Myeloma (MM) Patients (pts) Treated by Tandem Autologous (Auto)/Allogeneic (Allo) Stem Cell Transplantation (SCT) : Retrospective Study of the Société Française de Greffe de Moelle Thérapie Cellulaire (SFGM-TC).
Authors: Claire Fabre, Serge Koscielny, Jean-Luc Harousseau, Mohamad Mohty, Didier Blaise, Noël Milpied, Bernard Rio, Mauricette Michallet, Thierry Facon, Jean-Paul Vernant, Agnès Buzyn, Gérard Socié, Jean-Yves Cahn, Natacha Maillard, Jacques-Olivier Bay, Jean-Henri Bourhis
Journal: Blood (2009)
Serum Uric Acid Levels during Allogeneic Hematopoeitic Cell Transplantation and Subsequent Graft Versus Host Disease
Authors: Albert C Yeh, Thomas R. Spitzer, Yi-Bin Chen, Steven McAfee, Karen K. Ballen, Eyal C. Attar, Amir T. Fathi, Bimalangshu R. Dey
Journal: Blood (2014)
Central Morphology Review of Childhood Bone Marrow Failure in Japan
Authors: Asahito Hama, Manabe Atsushi, Daisuke Hasegawa, Kazue Nozawa, Yusuke Okuno, Masahiro Irie, Hideki Muramatsu, Yoshiyuki Takahashi, Kenichiro Watanabe, Akira Ohara, Masafumi Ito, Seiji Kojima
Journal: Blood (2014)
Dinaciclib (SCH 727965) and Ofatumumab for the Treatment of Relapsed and Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): Results of a Phase 1b/2 Study
Authors: Jeffrey Alan Jones, Susan Geyer, Leslie A. Andritsos, Farrukh Awan, Joseph M Flynn, Kami J. Maddocks, Anissa Bingman, Amy J. Johnson, Nyla A. Heerema, Cathy Brookfield, John C. Byrd, Michael R. Grever
Journal: Blood (2014)
Idiopathic Cytopenia of Undetermined Significance (ICUS): Impact of Flow Cytometry Immunophenotyping (FCI) in the Diagnosis of Myelodysplastic Syndrome (MDS) When Morphology Is Not Conclusive.
Authors: Patricia Font, Dolores Subira, Javier Loscertales, Eva Arranz, Arancha Alonso, M. Angeles Perez-Saenz, Antonio Escudero, Jose Maria Fernandez-Rañada, Teresa Vallespi
Journal: Blood (2007)
Evaluation of the Prothrombotic Risk Factors in Children with Leukemia
Authors: Aysegul Unuvar, Arzu Akcay, Ebru T Saribeyoglu, Deniz Tugcu, Zeynep Karakas, Gulyuz Ozturk, Sema Anak, Leyla Agaoglu, Omer Devecioglu
Journal: Blood (2008)
Therapeutic role of dual inhibition of cyclooxygenase-2 and 5-lipoxygenase in the colonic tumorigenesis promoted by cigarette smoke
Authors: Yi-Ni Ye, Vivian Y. Shin, Chi-Hin Cho
Journal: Cancer Research (2004)

3862  Previous study indicated that the arachidonic acid-metabolizing enzymes cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) are over-expressed during the process of colonic adenoma formation promoted by cigarette smoke and have been implicated as mediators of tumor development. The aim of the present study was to investigate whether there exists a relationship between COX-2 and 5-LOX, and also the anti-carcinogenic effect of dual inhibition of COX-2 and 5-LOX in the colonic tumorigenesis promoted by cigarette smoke. Our results showed that pretreated the colon cancer cells with cigarette smoke extract significantly promoted the xenograft growth of cancer cells in nude mice. Inhibition of COX-2 or 5-LOX by SC-58635 or MK886, respectively, reduced the tumor size of colon cancer in these animals by 31% and 54%. In the COX-2 inhibitor treated group, the PGE2 level was decreased about 30% while the LTB4 level was increased about 3 folds when compared to the control group. In contrast, in the MK886 treated group, the LTB4 level was reduced about 60% and the PGE2 level was not changed when compared to the control group. However, combined treatment with the COX-2 and 5-LOX inhibitors, the tumor growth of colon cancer xenograft promoted by cigarette smoke extract was further inhibited when compared with those treated with either SC-58635 or MK886 alone. This was accompanied by the down-regulation of PGE2 and LTB4 in the tumors. Taken together, these results indicated that inhibition of COX may lead to a shunt of the arachidonic metabolism towards the leukotriene pathway during colonic tumorigenesis promoted by cigarette smoke. Suppression of 5-LOX did not have such shunting of arachidonic acid metabolism and produced better response on inhibition of tumor growth. Furthernore, drugs which are able to block equally the synthesis or activation of both COX-2 and 5-LOX, should not only present a superior anti-cancer profile but also fewer side effects than the selective COX-2 and 5-LOX inhibitors when higher doses are needed for individual drug to achieve the similar anticancer effect.
Unexpected High Frequency of GATA2 Mutations in Children with Non-Familial MDS and Monosomy 7
Authors: Shinsuke Hirabayashi, Brigitte Strahm, Sandra Urbaniak, Axel Karow, Annamaria Cseh, Marry Van Den Heuvel, Selin Aytag, Claudia Wehr, Ales Janda, Jan Stary, Henrik Hasle, Michael Dworzak, Markus Schmugge, Franco Locatelli, Barbara De Moerloose, Albert Catala, Owen Smith, Irith Baumann, Gudrun Göhring, Brigitte Schlegelberger, Charlotte M Niemeyer, Marcin W Wlodarski
Journal: Blood (2012)
BCL-W has a fundamental role in B cell survival and lymphomagenesis
Authors: Clare M. Adams, Annette S. Kim, Ramkrishna Mitra, John K. Choi, Jerald Z. Gong, Christine M. Eischen
Journal: Journal of Clinical Investigation (2017)

Compromised apoptotic signaling is a prerequisite for tumorigenesis. The design of effective therapies for cancer treatment depends on a comprehensive understanding of the mechanisms that govern cell survival. The antiapoptotic proteins of the BCL-2 family are key regulators of cell survival and are frequently overexpressed in malignancies, leading to increased cancer cell survival. Unlike BCL-2 and BCL-XL, the closest antiapoptotic relative BCL-W is required for spermatogenesis, but was considered dispensable for all other cell types. Here, however, we have exposed a critical role for BCL-W in B cell survival and lymphomagenesis. Loss of Bcl-w conferred sensitivity to growth factor deprivation-induced B cell apoptosis. Moreover, Bcl-w loss profoundly delayed MYC-mediated B cell lymphoma development due to increased MYC-induced B cell apoptosis. We also determined that MYC regulates BCL-W expression through its transcriptional regulation of specific miR. BCL-W expression was highly selected for in patient samples of Burkitt lymphoma (BL), with 88.5% expressing BCL-W. BCL-W knockdown in BL cell lines induced apoptosis, and its overexpression conferred resistance to BCL-2 family-targeting BH3 mimetics. Additionally, BCL-W was overexpressed in diffuse large B cell lymphoma and correlated with decreased patient survival. Collectively, our results reveal that BCL-W profoundly contributes to B cell lymphoma, and its expression could serve as a biomarker for diagnosis and aid in the development of better targeted therapies.