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https://www.readbyqxmd.com/read/28096095/functional-role-and-therapeutic-targeting-of-p21-associated-kinase-4-pak4-in-multiple-myeloma
#1
Mariateresa Fulciniti, Joaquin Martinez-Lopez, William Senapedis, Stefania Oliva, Rajya Lakshmi Bandi, Nicola Amodio, Yan Xu, Raphael L Szalat, Annamaria Gulla, Mehmet K Samur, Aldo Roccaro, Maria Linares, Michele Cea, Erkan Baloglu, Christian Argueta, Yosef Landesman, Sharon Shacham, Siyuan Liu, Monica Schenone, Shiaw-Lin Wu, Barry Karger, Rao Prabhala, Kenneth C Anderson, Nikhil C Munshi
Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4), and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-ERK pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28096094/platelet-cd34-expression-and-%C3%AE-%C3%AE-granule-abnormalities-in-gfi1b-and-runx1-related-familial-bleeding-disorders
#2
Anna E Marneth, Waander L van Heerde, Konnie M Hebeda, Britta A P Laros-van Gorkom, Wideke Barteling, Brigith Willemsen, Aniek O de Graaf, Annet Simons, Joop H Jansen, Frank Preijers, Marjolijn C Jongmans, Bert A van der Reijden
No abstract text is available yet for this article.
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28096093/lymphangiogenesis-is-a-feature-of-acute-gvhd-and-vegfr-3-inhibition-protects-against-experimental-gvhd
#3
Sarah Mertlitz, Yu Shi, Martina Kalupa, Carsten Grötzinger, Jörg Mengwasser, Katarina Riesner, Steffen Cordes, Sefer Elezkurtaj, Olaf Penack
Lymph vessels play a crucial role for immune reactions in health and disease. In oncology the inhibition of lymphangiogenesis is an established therapeutic concept to reduce metastatic spreading of tumor cells. During allogeneic tissue transplantation the inhibition of lymphangiogenesis has been successfully used to attenuate graft rejection. Despite its critical importance for tumor growth, allo-immune responses and inflammation, the role of lymphangiogenesis has not been investigated during allogeneic hematopoietic stem cell transplantation (allo-HSCT)...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28096092/initiation-of-acute-graft-versus-host-disease-by-angiogenesis
#4
Katarina Riesner, Yu Shi, Angela Jacobi, Martin Kraeter, Martina Kalupa, Aleixandria McGearey, Sarah Mertlitz, Steffen Cordes, Jens-Florian Schrezenmeier, Jörg Mengwasser, Sabine Westphal, Daniel Perez-Hernandez, Clemens Schmitt, Gunnar Dittmar, Jochen Guck, Olaf Penack
The inhibition of inflammation-associated angiogenesis ameliorates inflammatory diseases by reducing the recruitment of tissue infiltrating leukocytes. However, it is not known if angiogenesis has an active role during the initiation of inflammation or if it is merely a secondary effect occurring in response to stimuli by tissue infiltrating leukocytes. Here we show that angiogenesis precedes leukocyte infiltration in experimental models of inflammatory bowel disease and acute graft-versus-host disease (GVHD)...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28096091/use-of-hematopoietic-cell-transplantation-for-patients-with-myelodysplastic-syndrome-and-chronic-myelomonocytic-leukemia
#5
Theo de Witte, David Bowen, Marie Robin, Luca Malcovati, Dietger Niederwieser, Ibrahim Yakoub-Agha, Ghulam J Mufti, Pierre Fenaux, Guillermo Sanz, Rodrigo Martino, Emilio Paolo Alessandrino, Francesco Onida, Argiris Symeonidis, Jakob Passweg, Guido Kobbe, Arnold Ganser, Uwe Platzbecker, Jürgen Finke, Michel van Gelder, Arjan A van de Loosdrecht, Per Ljungman, Reinhard Stauder, Liisa Volin, H Joachim Deeg, Corey Cutler, Wael Saber, Richard Champlin, Sergio Giralt, Claudio Anasetti, Nicolaus Kröger
No abstract text is available yet for this article.
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28096090/how-i-manage-ibrutinib-refractory-chronic-lymphocytic-leukemia
#6
Jennifer A Woyach
The introduction of the Bruton's Tyrosine Kinase inhibitor ibrutinib has dramatically changed the management of chronic lymphocytic leukemia. Although responses have been durable in the majority of patients, relapses do occur, especially in the high risk patient population. Most relapses occur as the result of acquired mutations in BTK and PLCG2, which may facilitate success with alternative targeted therapies. As outcomes following ibrutinib relapse have been reported to be poor, specific strategies are needed for this patient population...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28096089/tolerogenic-interactions-between-cd8-dendritic-cells-and-nkt-cells-prevent-rejection-of-bone-marrow-and-organ-grafts
#7
David Hongo, Xiaobin Tang, Xiangyue Zhang, Edgar G Engleman, Samuel Strober
The combination of total lymphoid irradiation and anti-T cell antibodies safely induces immune tolerance to combined hematopoietic cell and organ allografts in humans. Our mouse model required host natural killer T (NKT) cells to induce tolerance. Since NKT cells normally depend on signals from CD8+ dendritic cells (DCs) for their activation, we used the mouse model to test the hypothesis that after lymphoid irradiation host CD8+DCs play a requisite role in tolerance induction through interactions with NKT cells...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28096088/how-i-treat-acquired-aplastic-anemia
#8
Andrea Bacigalupo
Acquired severe aplastic anemia (SAA) is a rare hematologic disease associated with significant morbidity and mortality. Immune destruction of hemopoietic stem cells, plays an important role in the pathogenesis, as shown by successful treatment with immunosuppressive agents (IST), leading to transfusion independence, or complete recovery of peripheral blood counts, in a proportion of patients. Growth factors, can be combined with IST, and may improve response rates, as recently shown with thrombopoietin analogs...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28096087/diffuse-large-b-cell-lymphoma-genotyping-on-the-liquid-biopsy
#9
Davide Rossi, Fary Diop, Elisa Spaccarotella, Sara Monti, Manuela Zanni, Silvia Rasi, Clara Deambrogi, Valeria Spina, Alessio Bruscaggin, Chiara Favini, Roberto Serra, Antonio Ramponi, Renzo Boldorini, Robin Foa', Gianluca Gaidano
Accessible and real-time genotyping for diagnostic, prognostic or treatment purposes is increasingly impelling in diffuse large B-cell lymphoma (DLBCL). Cell-free DNA (cfDNA) is shed into the blood by tumor cells undergoing apoptosis and can be used as source of tumor DNA for the identification of DLBCL mutations, clonal evolution, and genetic mechanisms of resistance. Here we aimed at tracking the basal DLBCL genetic profile and its modification upon treatment using plasma cfDNA. Ultra-deep targeted next generation sequencing of pre-treatment plasma cfDNA from DLBCL patients correctly discovered DLBCL-associated mutations that were represented in >20% of the alleles of the tumor biopsy with a >90% sensitivity and a ~100% specificity...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28096086/platelets-activate-a-pathogenic-response-to-blood-stage-plasmodium-infection-but-not-a-protective-immune-response
#10
Irene Gramaglia, Joyce Velez, Valery Combes, Georges E R Grau, Melanie Wree, Henri C van der Heyde
Clinical studies indicate that thrombocytopenia correlates with the development of severe falciparum malaria, suggesting that platelets either contribute to control of parasite replication possibly as innate parasite killer cells or function in eliciting pathogenesis. Removal of platelets by anti-CD41 mAb treatment, platelet inhibition by aspirin, and adoptive transfer of WT platelets to CD40-KO mice, which do not control parasite replication, resulted in similar parasitemia compared with control mice. Human platelets at a physiological ratio of 1 platelet to 9 RBCs did not inhibit the in vitro development or replication of blood-stage P...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28087540/international-evidence-based-consensus-diagnostic-criteria-for-hhv-8-negative-idiopathic-multicentric-castleman-disease
#11
David C Fajgenbaum, Thomas S Uldrick, Adam Bagg, Dale Frank, David Wu, Gordan Srkalovic, David Simpson, Amy Y Liu, David Menke, Shanmuganathan Chandrakasan, Mary Jo Lechowicz, Raymond S M Wong, Sheila Pierson, Michele Paessler, Jean-François Rossi, Makoto Ide, Jason Ruth, Michael Croglio, Alexander Suarez, Vera Krymskaya, Amy Chadburn, Gisele Colleoni, Sunita Nasta, Raj Jayanthan, Christopher S Nabel, Corey Casper, Angela Dispenzieri, Alexander Fosså, Dermot Kelleher, Razelle Kurzrock, Peter Voorhees, Ahmet Dogan, Kazuyuki Yoshizaki, Frits van Rhee, Eric Oksenhendler, Elaine S Jaffe, Kojo S J Elenitoba-Johnson, Megan S Lim
Human Herpesvirus-8(HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction due to a cytokine storm often including interleukin-6. iMCD accounts for one-third to one-half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, as no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders...
January 13, 2017: Blood
https://www.readbyqxmd.com/read/28087539/quantitative-stability-of-hematopoietic-stem-and-progenitor-cell-clonal-output-in-transplanted-rhesus-macaques
#12
Samson J Koelle, Diego A Espinoza, Chuanfeng Wu, Jason Xu, Rong Lu, Brian Li, Robert E Donahue, Cynthia E Dunbar
Autologous transplantation of hematopoietic stem and progenitor cells lentivirally labeled with unique oligonucleotide barcodes flanked by sequencing primer targets enables quantitative assessment of the self-renewal and differentiation patterns of these cells in a myeloablative rhesus macaque model. Compared with other approaches to clonal tracking, this approach is highly quantitative and reproducible. We documented very stable multipotent long-term hematopoietic clonal output of monocytes, granulocytes, B cells and T cells from a polyclonal pool of hematopoietic stem and progenitor cells in four macaques followed for up to 49 months post-transplantation...
January 13, 2017: Blood
https://www.readbyqxmd.com/read/28087538/bcap-inhibits-proliferation-and-differentiation-of-myeloid-progenitors-in-the-steady-state-and-during-demand-situations
#13
Jeffrey M Duggan, Matthew B Buechler, Rebecca M Olson, Tobias M Hohl, Jessica A Hamerman
B cell adaptor for PI3-kinase (BCAP) is a signaling adaptor expressed in mature hematopoietic cells including monocytes and neutrophils. Here we investigated the role of BCAP in the homeostasis and development of these myeloid lineages. BCAP(-/-) mice had more bone marrow (BM) monocytes than WT mice, and in mixed WT:BCAP(-/-) BM chimeras, monocytes and neutrophils skewed towards BCAP(-/-) origin, showing a competitive advantage for BCAP(-/-) myeloid cells. BCAP was expressed in bone marrow hematopoietic progenitors, including LSK (Lineage(-)Sca1(+)cKit(+)), CMP (Common Myeloid Progenitor) and GMP (Granulocyte/Macrophage Progenitor) cells...
January 13, 2017: Blood
https://www.readbyqxmd.com/read/28082445/p53-related-protein-kinase-confers-poor-prognosis-and-represents-a-novel-therapeutic-target-in-multiple-myeloma
#14
Teru Hideshima, Francesca Cottini, Yoshihisa Nozawa, Hyuk-Soo Seo, Hiroto Ohguchi, Mehmet K Samur, Diana Cirstea, Naoya Mimura, Yoshikazu Iwasawa, Paul G Richardson, Nikhil C Munshi, Dharminder Chauhan, Walter Massefski, Teruhiro Utsugi, Sirano Dhe-Paganon, Kenneth C Anderson
p53-related protein kinase (TP53RK, also known as PRPK) is an upstream kinase which phosphorylates (Ser15) and mediates p53 activity. Here we show that TP53RK confers poor prognosis in MM patients; and conversely, that TP53RK knockdown inhibits p53 phosphorylation and triggers multiple myeloma (MM) cell apoptosis, associated with downregulation of c-Myc and E2F-1-mediated upregulation of pro-apoptotic Bim. We further demonstrate that TP53RK downregulation also triggers growth inhibition in p53-deficient (KMS-11) and p53-mutant (U266) MM cell lines, and identify novel downstream targets of TP53RK including ribonucleotide reductase-1, telomerase reverse transcriptase, and cyclin dependent kinase inhibitor 2C (CDKN2C)...
January 12, 2017: Blood
https://www.readbyqxmd.com/read/28082444/mutational-landscape-and-response-are-conserved-in-peripheral-blood-of-aml-and-mds-patients-during-decitabine-therapy
#15
Eric J Duncavage, Geoffrey L Uy, Allegra A Petti, Christopher A Miller, Yi-Shan Lee, Bevan Tandon, Feng Gao, Catrina C Fronick, Michelle O'Laughlin, Robert S Fulton, Richard K Wilson, Meagan A Jacoby, Amanda F Cashen, Lukas D Wartman, Matthew J Walter, Peter Westervelt, Daniel C Link, John F DiPersio, Timothy J Ley, John S Welch
No abstract text is available yet for this article.
January 12, 2017: Blood
https://www.readbyqxmd.com/read/28082443/a-novel-ptpn1-splice-variant-upregulates-jak-stat-activity-in-classical-hodgkin-s-lymphoma-cells
#16
Malena Zahn, Ralf Marienfeld, Ingo Melzner, Janine Heinrich, Benjamin Renner, Silke Wegener, Anna Mießner, Thomas F E Barth, Karola Dorsch, Silke Brüderlein, Peter Möller
Chronic activation of the Janus kinase (JAK)/ Signal Transducer and Activator of Transcription (STAT) signaling pathways is a hallmark of a variety of B cell lymphomas including classical Hodgkin's lymphoma (cHL). Constitutive JAK/STAT signaling is crucial for survival and proliferation of Hodgkin/Reed-Sternberg (HRS) cells, the malignant cells of cHL. Although the molecular basis of this constitutive JAK/STAT signaling in cHL has not been completely understood, accumulating reports highlight the role of an inactivation or reduced expression of negative JAK/STAT regulators like Silencer Of Cell Signaling 1 (SOCS1) or Protein-Tyrosine Phosphatase 1B (PTP1B) in this process...
January 12, 2017: Blood
https://www.readbyqxmd.com/read/28082442/rhig-prophylaxis-is-not-influenced-by-fcgr2-3-polymorphisms-involved-in-red-blood-cell-clearance
#17
Tamara C Stegmann, Barbera Veldhuisen, Sietse Q Nagelkerke, Dian Winkelhorst, Henk Schonewille, Esther P Verduin, Taco W Kuijpers, Masja de Haas, Gestur Vidarsson, C Ellen van der Schoot
No abstract text is available yet for this article.
January 12, 2017: Blood
https://www.readbyqxmd.com/read/28082441/determinants-of-fatal-bleeding-during-induction-therapy-for-acute-promyelocytic-leukemia-in-the-atra-era
#18
Simon Mantha, Debra A Goldman, Sean M Devlin, Ju-Whei Lee, Diana Zannino, Marnie Collins, Dan Douer, Harry J Iland, Mark R Litzow, Eytan M Stein, Frederick R Appelbaum, Richard A Larson, Richard Stone, Bayard L Powell, Susan Geyer, Kristina Laumann, Jacob M Rowe, Harry Erba, Steven Coutre, Megan Othus, Jae H Park, Peter H Wiernik, Martin S Tallman
Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy. Uncertainty remains as to which markers of bleeding risk are independent predictors. Drawing from five large clinical trials that included ATRA as part of induction, we assessed known determinants of bleeding at baseline and evaluated them as potential predictors of hemorrhagic death (HD) in the first 30 days of treatment. The studies included were: ALLG APML3 (single arm of ATRA + idarubicin ± prednisone), ALLG APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone), CALGB C9710 (single arm of ATRA + cytarabine + daunorubicin), ECOG-ACRIN E2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA) and SWOG S0521 (single arm induction of ATRA + cytarabine + daunorubicin)...
January 12, 2017: Blood
https://www.readbyqxmd.com/read/28077418/a-novel-humanized-mouse-model-with-significant-improvement-of-class-switched-antigen-specific-antibody-production
#19
Hua Yu, Chiara Borsotti, Jean-Nicolas Schickel, Shu Zhu, Till Strowig, Elizabeth E Eynon, Davor Frleta, Cagan Gurer, Andrew J Murphy, George D Yancopoulos, Eric Meffre, Markus G Manz, Richard A Flavell
Humanized mice are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, the existing models cannot support robust adaptive immune responses, especially the generation of class-switched, antigen-specific antibody responses. Here we describe a new mouse strain, in which human IL6 gene encoding the cytokine that is important for B and T cell differentiation was knocked into its respective mouse locus. The provision of human IL6 not only enhanced thymopoiesis and periphery T-cell engraftment, but also significantly increased class switched memory B cells and serum IgG...
January 11, 2017: Blood
https://www.readbyqxmd.com/read/28077417/aid-is-a-key-regulator-of-myeloid-erythroid-differentiation-and-dna-methylation-in-hematopoietic-stem-progenitor-cells
#20
Hiroyoshi Kunimoto, Anna Sophia McKenney, Cem Meydan, Kaitlyn Shank, Abbas Nazir, Franck Rapaport, Benjamin Durham, Francine E Garrett-Bakelman, Elodie Pronier, Alan H Shih, Ari Melnick, Jayanta Chaudhuri, Ross L Levine
Recent studies have reported activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies and hematopoietic specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating TET2 as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of AID loss in hematopoiesis and myeloid transformation remains to be investigated...
January 11, 2017: Blood
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