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https://www.readbyqxmd.com/read/28518222/the-effect-of-initial-molecular-profile-on-response-to-recombinant-interferon-%C3%AE-rifn%C3%AE-treatment-in-early-myelofibrosis
#1
Richard T Silver, Ariella C Barel, Elena Lascu, Ellen K Ritchie, Gail J Roboz, Paul J Christos, Attilio Orazi, Duane C Hassane, Wayne Tam, Nicholas C P Cross
BACKGROUND: Although recombinant interferon-α (rIFNα) effectively treats patients with early myelofibrosis, the effect of driver and high molecular risk (HMR) mutations has not been considered. In this phase 2 study, for the first time, the authors correlate response to rIFNα treatment with driver and HMR mutations. METHODS: Patients were diagnosed using World Health Organization or International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria...
May 18, 2017: Cancer
https://www.readbyqxmd.com/read/28505169/molecular-basis-of-targeted-therapy-in-t-nk-cell-lymphoma-leukemia-a-comprehensive-genomic-and-immunohistochemical-analysis-of-a-panel-of-33-cell-lines
#2
Rufino Mondejar, Cristina Pérez, Arantza Onaindia, Nerea Martinez, Julia González-Rincón, Helena Pisonero, Jose Pedro Vaqué, Laura Cereceda, Miguel Santibañez, Margarita Sánchez-Beato, Miguel Angel Piris
T and NK-cell lymphoma is a collection of aggressive disorders with unfavorable outcome, in which targeted treatments are still at a preliminary phase. To gain deeper insights into the deregulated mechanisms promoting this disease, we searched a panel of 31 representative T-cell and 2 NK-cell lymphoma/leukemia cell lines for predictive markers of response to targeted therapy. To this end, targeted sequencing was performed alongside the expression of specific biomarkers corresponding to potentially activated survival pathways...
2017: PloS One
https://www.readbyqxmd.com/read/28500170/jak2-inhibitors-for-myeloproliferative-neoplasms-what-is-next
#3
Prithviraj Bose, Srdan Verstovsek
Since its approval in 2011, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant/intolerant polycythemia vera (PV) is steadily increasing. A number of other JAK2 inhibitors have entered clinical testing, but none has been approved yet, and many discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, where survival is short...
May 12, 2017: Blood
https://www.readbyqxmd.com/read/28461505/suppressors-and-activators-of-jak-stat-signaling-at-diagnosis-and-relapse-of-acute-lymphoblastic-leukemia-in-down-syndrome
#4
Omer Schwartzman, Angela Maria Savino, Michael Gombert, Chiara Palmi, Gunnar Cario, Martin Schrappe, Cornelia Eckert, Arend von Stackelberg, Jin-Yan Huang, Michal Hameiri-Grossman, Smadar Avigad, Geertruy Te Kronnie, Ifat Geron, Yehudit Birger, Avigail Rein, Giulia Zarfati, Ute Fischer, Zohar Mukamel, Martin Stanulla, Andrea Biondi, Giovanni Cazzaniga, Amedeo Vetere, Bridget K Wagner, Zhu Chen, Sai-Juan Chen, Amos Tanay, Arndt Borkhardt, Shai Izraeli
Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DS-ALLs...
May 16, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28436280/persistent-foot-ulcer-due-to-ruxolitinib-therapy-for-primary-myelofibrosis
#5
Michael Del Rosario, Henry Tsai, Constantin A Dasanu
Primary myelofibrosis is characterized by bone marrow fibrosis, splenomegaly and presence of JAK-2 V617F mutation in more than 90% of patients. Ruxolitinib is a Janus kinase inhibitor used for the treatment of primary myelofibrosis. We describe herein a persistent foot ulcer development attributed to ruxolitinib therapy. We are unaware of any previous reports of this phenomenon in the scientific literature. A thorough examination of the lower extremities is perhaps necessary before initiating this oral agent...
January 1, 2017: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/28410228/identification-of-a-novel-functional-jak1-s646p-mutation-in-acute-lymphoblastic-leukemia
#6
Qian Li, Botao Li, Liangding Hu, Hongmei Ning, Min Jiang, Danhong Wang, Tingting Liu, Bin Zhang, Hu Chen
The survival rate of childhood acute lymphoblastic leukemia (ALL) is approaching 90%, while the prognosis of adults remains poor due to the limited therapeutic approaches. In order to identify new targets for ALL, we performed whole-exome sequencing on four adults with B-ALL and discovered a somatic JAK1 S646P mutation. Sanger sequencing of JAK1 was conducted on 53 ALL patients, and two cases exhibited A639G and P960S mutations separately. Functional studies demonstrated that only JAK1 S646P mutation could activate multiple signaling pathways, drive cytokine-independent cell growth, and promote proliferation of malignant cells in nude mice...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28409351/inflammation-and-fibrosis-in-polycystic-kidney-disease
#7
Cheng Jack Song, Kurt A Zimmerman, Scott J Henke, Bradley K Yoder
Polycystic kidney disease (PKD) is a commonly inherited disorder characterized by cyst formation and fibrosis (Wilson, N Engl J Med 350:151-164, 2004) and is caused by mutations in cilia or cilia-related proteins, such as polycystin 1 or 2 (Oh and Katsanis, Development 139:443-448, 2012; Kotsis et al., Nephrol Dial Transplant 28:518-526, 2013). A major pathological feature of PKD is the development of interstitial inflammation and fibrosis with an associated accumulation of inflammatory cells (Grantham, N Engl J Med 359:1477-1485, 2008; Zeier et al...
2017: Results and Problems in Cell Differentiation
https://www.readbyqxmd.com/read/28395559/management-of-myelofibrosis-jak-inhibition-and-beyond
#8
Maximilian Stahl, Amer M Zeidan
Myelofibrosis (MF) is characterized by bone marrow fibrosis with subsequent extramedullary hematopoiesis and abnormal cytokine expression leading to splenomegaly, constitutional symptoms and cytopenias. The discovery of the JAK2 V617F mutation in the majority of MF patients has been followed by significant progress in drug development for MF. Areas covered: In this article, we review advances in the understanding of the underlying disease biology, prognostic assessment and therapeutic modalities for MF. We provide clinical trial evidence behind using the JAK2 inhibitor ruxolitinib, erythropoiesis stimulating agents, androgens, immunomodulatory drugs, interferon, cytoreductive drugs and hypomethylating agents in MF...
April 26, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28356514/cytokine-receptor-signaling-is-required-for-the-survival-of-alk-anaplastic-large-cell-lymphoma-even-in-the-presence-of-jak1-stat3-mutations
#9
Jing Chen, Yong Zhang, Michael N Petrus, Wenming Xiao, Alina Nicolae, Mark Raffeld, Stefania Pittaluga, Richard N Bamford, Masao Nakagawa, Sunny Tianyi Ouyang, Alan L Epstein, Marshall E Kadin, Annarose Del Mistro, Richard Woessner, Elaine S Jaffe, Thomas A Waldmann
Activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) mutations have been discovered in many T-cell malignancies, including anaplastic lymphoma kinase (ALK)(-) anaplastic large cell lymphomas (ALCLs). However, such mutations occur in a minority of patients. To investigate the clinical application of targeting JAK for ALK- ALCL, we treated ALK- cell lines of various histological origins with JAK inhibitors. Interestingly, most exogenous cytokine-independent cell lines responded to JAK inhibition regardless of JAK mutation status...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28340183/crlf2-positive-b-cell-acute-lymphoblastic-leukemia-in-adult-patients-a-single-institution-experience
#10
Sergej Konoplev, Xinyan Lu, Marina Konopleva, Nitin Jain, Juan Ouyang, Maitrayee Goswami, Kathryn G Roberts, Marc Valentine, Charles G Mullighan, Carlos Bueso-Ramos, Patrick A Zweidler-McKay, Jeffrey L Jorgensen, Sa A Wang
Objectives: Cytokine receptor-like factor 2 ( CRLF2 ) rearrangement is found in approximately 50% of pediatric Ph-like B-cell acute lymphoblastic leukemia (B-ALL), and around 50% of CRLF2 + cases harbor JAK mutations. We analyzed CRLF2 expression and studied its correlation with CRLF2 rearrangement in adult patients with B-ALL. Methods: Multiparameter flow cytometry (MFC) was performed consecutively in 126 patients. Results: CRLF2 overexpression was detected in 30 (27%) patients, 28 (41%) of 69 patients with B-ALL not otherwise specified, 14 (21%) of 67 untreated patients, and 16 (27%) of 59 patients with relapsed B-ALL, with the highest among Hispanic patients (25/55, 45%)...
April 1, 2017: American Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28324831/primary-and-acquired-resistance-to-pd-1-pd-l1-blockade-in-cancer-treatment
#11
REVIEW
Qiaohong Wang, Xia Wu
PD-1/PD-L1 blockade appears to be a very promising immunotherapy with significant clinical benefits and durable responses in multiple tumor types. However, the effectual clinical benefits of PD-1/PD-L1 blockade are hampered by a high rate of primary resistance, where patients do not respond to PD-1/PD-L1 blockade initially. And more distressingly, most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms underlying primary and acquired resistance to PD-1/PD-L1 blockade have remained ambiguous...
May 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28284718/novel-jak3-activating-mutations-in-extranodal-nk-t-cell-lymphoma-nasal-type
#12
Sung H Sim, Soyeon Kim, Tae M Kim, Yoon K Jeon, Soo J Nam, Yong-Oon Ahn, Bhumsuk Keam, Hyun H Park, Dong-Wan Kim, Chul W Kim, Dae S Heo
Inhibition of the Janus kinase (JAK)-STAT pathway has been implicated as a treatment option for extranodal natural killer/T-cell lymphoma, nasal type (NTCL). However, JAK-STAT pathway alterations in NTCL are variable, and the efficacy of JAK-STAT pathway inhibition has been poorly evaluated. JAK3 mutation and STAT3 genetic alterations were investigated by direct sequencing and immunohistochemistry in 84 patients with newly diagnosed NTCL. Five of 71 patients with NTCL (7.0%) had JAK3 mutations in the pseudokinase domain: two JAK3(A573V), two JAK3(H583Y), and one JAK3(G589D) mutation...
March 8, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28277287/the-promise-of-janus-kinase-inhibitors-in-the-treatment-of-hematological-malignancies
#13
REVIEW
Emilee Senkevitch, Scott Durum
The Janus kinases (JAK) are a family of kinases that play an essential role in cytokine signaling and are implicated in the pathogenesis of autoimmune diseases and hematological malignancies. As a result, the JAKs have become attractive therapeutic targets. The discovery of a JAK2 point mutation (JAK2 V617F) as the main cause of polycythemia vera lead to the development and FDA approval of a JAK1/2 inhibitor, ruxolitinib, in 2011. This review focuses on the various JAK and associated components aberrations implicated in myeloproliferative neoplasms, leukemias, and lymphomas...
October 27, 2016: Cytokine
https://www.readbyqxmd.com/read/28253502/short-stature-in-a-boy-with-multiple-early-onset-autoimmune-conditions-due-to-a-stat3-activating-mutation-could-intracellular-growth-hormone-signalling-be-compromised-%C3%A2
#14
Hana Sediva, Petra Dusatkova, Veronika Kanderova, Barbora Obermannova, Jana Kayserova, Lucie Sramkova, Dana Zemkova, Lenka Elblova, Michal Svaton, Radana Zachova, Stanislava Kolouskova, Eva Fronkova, Zdenek Sumnik, Anna Sediva, Jan Lebl, Stepanka Pruhova
BACKGROUND: Germline STAT3 gain-of-function (GOF) mutations cause multiple endocrine and haematologic autoimmune disorders, lymphoproliferation, and growth impairment. As the JAK-STAT pathway is known to transduce the growth hormone (GH) signalling, and STAT3 interacts with STAT5 in growth regulation, we hypothesised that short stature in STAT3 GOF mutations results mostly from GH insensitivity via involving activation of STAT5. CASE REPORT: A boy with a novel STAT3 c...
March 2, 2017: Hormone Research in Pædiatrics
https://www.readbyqxmd.com/read/28214593/jak-stat-pathway-directed-therapy-of-t-cell-leukemia-lymphoma-inspired-by-functional-and-structural-genomics
#15
REVIEW
Thomas A Waldmann
Abnormal activation of the γc cytokine JAK/STAT signaling pathway assessed by STAT3 or STAT5b phosphorylation was present in a proportion of many T-cell malignancies. Activating mutations of STAT3/STAT5b and JAK1/3 were present in some but not in all cases with constitutive signaling pathway activation. Using shRNA analysis pSTAT malignant T-cell lines were addicted to JAKs/STATs whether they were mutated or not. Activating JAK/STAT mutations were not sufficient to support leukemic cell proliferation but only augmented upstream pathway signals...
February 15, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28202754/jak-stat-signaling-pathways-and-inhibitors-affect-reversion-of-envelope-mutated-hiv-1
#16
Yudong Quan, Hongtao Xu, Yingshan Han, Thibault Mesplède, Mark A Wainberg
HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that many of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, which was followed by reversion to the wild type. However, the activation of JAK-STAT signaling pathways caused the inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in their abilities to bind to the CD4 receptor...
May 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28167612/jak-mutations-as-escape-mechanisms-to-anti-pd-1-therapy
#17
Aurelien Marabelle, Sandrine Aspeslagh, Sophie Postel-Vinay, Jean-Charles Soria
JAK mutations could be one of the primary escape mechanisms to anti-PD-1/PD-L1 immunotherapy via impaired IFNγ signaling in cancer cells and could be used to identify patients unlikely to benefit from these treatments. Cancer Discov; 7(2); 128-30. ©2017 AACR.See related article by Shin et al., p. 188.
February 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28157215/identification-of-a-genetically-defined-ultra-high-risk-group-in-relapsed-pediatric-t-lymphoblastic-leukemia
#18
P Richter-Pechańska, J B Kunz, J Hof, M Zimmermann, T Rausch, O R Bandapalli, E Orlova, G Scapinello, J C Sagi, M Stanulla, M Schrappe, G Cario, R Kirschner-Schwabe, C Eckert, V Benes, J O Korbel, M U Muckenthaler, A E Kulozik
In the search for genes that define critical steps of relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) and can serve as prognostic markers, we performed targeted sequencing of 313 leukemia-related genes in 214 patients: 67 samples collected at the time of relapse and 147 at initial diagnosis. As relapse-specific genetic events, we identified activating mutations in NT5C2 (P=0.0001, Fisher's exact test), inactivation of TP53 (P=0.0007, Fisher's exact test) and duplication of chr17:q11.2-24.3 (P=0...
February 3, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28077299/anaplastic-lymphoma-kinase-alk-inhibitors-in-the-treatment-of-alk-driven-lung-cancers
#19
REVIEW
Robert Roskoski
Anaplastic lymphoma kinase is expressed in two-thirds of the anaplastic large-cell lymphomas as an NPM-ALK fusion protein. Physiological ALK is a receptor protein-tyrosine kinase within the insulin receptor superfamily of proteins that participates in nervous system development. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The amino-terminal portions of the ALK fusion proteins result in dimerization and subsequent activation of the ALK protein kinase domain that plays a key role in the pathogenesis of various tumors...
March 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28057939/activating-jak2-mutants-reveal-cytokine-receptor-coupling-differences-that-impact-outcomes-in-myeloproliferative-neoplasm
#20
H Yao, Y Ma, Z Hong, L Zhao, S A Monaghan, M-C Hu, L J Huang
Janus tyrosine kinase 2 (JAK2) mediates downstream signaling of cytokine receptors in all hematological lineages, yet constitutively active JAK2 mutants are able to drive selective expansion of particular lineage(s) in myeloproliferative neoplasm (MPN). The molecular basis of lineage specificity is unclear. Here, we show that three activating JAK2 mutants with similar kinase activities in vitro elicit distinctive MPN phenotypes in mice by differentially expanding erythroid vs granulocytic precursors. Molecularly, this reflects the differential binding of JAK2 mutants to cytokine receptors EpoR and GCSFR in the erythroid vs granulocytic lineage and the creation of unique receptor/JAK2 complexes that generate qualitatively distinct downstream signals...
January 31, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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