scholarly journals FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation

Blood ◽  
2015 ◽  
Vol 125 (12) ◽  
pp. 1936-1947 ◽  
Author(s):  
Thomas Oellerich ◽  
Sebastian Mohr ◽  
Jasmin Corso ◽  
Julia Beck ◽  
Carmen Döbele ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Survival ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Oncogenic Signaling ◽  
Flt3 Inhibitor ◽  
Key Points ◽  
Bruton Tyrosine Kinase ◽  
Cell Survival And Proliferation

Key Points Two novel transducer modules consisting of BTK in combination with either FLT3-ITD or TLR9 induce distinct oncogenic signaling programs. This study suggests subtype-specific treatment strategies, including BTK/FLT3 inhibitor combinations, and shows how TLR9 affects AML biology.

scholarly journals Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia

Blood ◽  
2019 ◽  
Vol 134 (15) ◽  
pp. 1257-1268 ◽  
Author(s):  
Yinghui Zhu ◽  
Xin He ◽  
Yi-Chun Lin ◽  
Haojie Dong ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Cell Survival ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Key Points ◽  
Survival And Growth ◽  
Inhibitor Treatment

Key Points High PRMT1 expression maintains MLL-r ALL cell survival and growth by regulating FLT3 methylation at R972/973. PRMT1 inhibition enhances ablation of MLL-r ALL by tyrosine kinase inhibitor treatment.

scholarly journals β2 integrin–derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis

Blood ◽  
2013 ◽  
Vol 121 (19) ◽  
pp. 3889-3899 ◽  
Author(s):  
Thomas Oellerich ◽  
Mark F. Oellerich ◽  
Michael Engelke ◽  
Silvia Münch ◽  
Sebastian Mohr ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Survival ◽  
Integrin Signaling ◽  
Β2 Integrin ◽  
Key Points ◽  
Stat Signaling ◽  
Signaling Axis ◽  
Cell Survival And Proliferation

Key Points Integrin signaling promotes proliferative signals in AML cells that are mediated by the kinase Syk and the transcription factors STAT3 and STAT5.

scholarly journals Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque–triggered thrombus formation in humans

Blood ◽  
2018 ◽  
Vol 131 (24) ◽  
pp. 2605-2616 ◽  
Author(s):  
Kristina Busygina ◽  
Janina Jamasbi ◽  
Till Seiler ◽  
Hans Deckmyn ◽  
Christian Weber ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Atherosclerotic Plaque ◽  
Kinase Inhibitors ◽  
Thrombus Formation ◽  
Drug Dosing ◽  
Key Points ◽  
Bruton Tyrosine Kinase ◽  
Platelet Thrombus ◽  
Btk Inhibitors

Key Points Btk inhibitors specifically block platelet thrombus formation on atherosclerotic plaque but spare physiologic hemostasis. Irreversible Btk inactivation in platelets incapable of enzyme resynthesis allows low intermittent drug dosing for antiatherothrombosis.

scholarly journals Oral Bruton tyrosine kinase inhibitors block activation of the platelet Fc receptor CD32a (FcγRIIA): a new option in HIT?

2019 ◽  
Vol 3 (23) ◽  
pp. 4021-4033 ◽  
Author(s):  
Luise Goldmann ◽  
Rundan Duan ◽  
Thorsten Kragh ◽  
Georg Wittmann ◽  
Christian Weber ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Platelet Activation ◽  
Kinase Inhibitors ◽  
Fc Receptor ◽  
Cross Linking ◽  
Key Points ◽  
Bruton Tyrosine Kinase

Key Points Six different BTKi’s blocked platelet activation in blood after FcγRIIA stimulation by cross-linking, anti-CD9 antibodies, or HIT serum. Established oral irreversible and novel reversible BTKi’s may offer a new option to treat HIT.

scholarly journals Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma

Blood ◽  
2017 ◽  
Vol 129 (16) ◽  
pp. 2224-2232 ◽  
Author(s):  
Ariela Noy ◽  
Sven de Vos ◽  
Catherine Thieblemont ◽  
Peter Martin ◽  
Christopher R. Flowers ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Marginal Zone ◽  
Single Agent ◽  
Unmet Need ◽  
Risk Profile ◽  
Marginal Zone Lymphoma ◽  
Key Points ◽  
Bcr Signaling ◽  
Bruton Tyrosine Kinase ◽  
Previously Treated

Key Points Single-agent ibrutinib induced durable remissions (ORR 48%) with a favorable benefit–risk profile in patients with previously treated MZL. Inhibition of BCR signaling with ibrutinib provides a treatment option without chemotherapy for an MZL population with high unmet need.

scholarly journals The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo

Blood ◽  
2012 ◽  
Vol 119 (5) ◽  
pp. 1182-1189 ◽  
Author(s):  
Sabine Ponader ◽  
Shih-Shih Chen ◽  
Joseph J. Buggy ◽  
Kumudha Balakrishnan ◽  
Varsha Gandhi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Survival ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Bruton Tyrosine Kinase ◽  
Targeted Agent

Abstract B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.

A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia

Blood ◽  
2013 ◽  
Vol 122 (7) ◽  
pp. 1222-1232 ◽  
Author(s):  
Guang Yang ◽  
Yangsheng Zhou ◽  
Xia Liu ◽  
Lian Xu ◽  
Yang Cao ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Somatic Mutation ◽  
Cell Killing ◽  
Waldenström Macroglobulinemia ◽  
Synergistic Inhibition ◽  
Waldenstrom Macroglobulinemia ◽  
Key Points ◽  
Bruton Tyrosine Kinase ◽  
Myd88 L265p ◽  
Stimulation Of

Key Points MYD88 L265P is a widely expressed somatic mutation in WM patients that supports NF-κB signaling through stimulation of BTK and IRAK 1/4. Combined suppression of BTK and IRAK in MYD88 L265P expressing WM cells promotes synergistic inhibition of NF-κB signaling and WM cell killing.

scholarly journals Targeted next-generation sequencing in blast phase myeloproliferative neoplasms

2018 ◽  
Vol 2 (4) ◽  
pp. 370-380 ◽  
Author(s):  
Terra L. Lasho ◽  
Mythri Mudireddy ◽  
Christy M. Finke ◽  
Curtis A. Hanson ◽  
Rhett P. Ketterling ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Sample Analysis ◽  
Blast Phase ◽  
Paired Sample ◽  
Targeted Next Generation Sequencing ◽  
Key Points ◽  
Generation Sequencing ◽  
Analysis Point

Key Points Mutation patterns in blast phase MPN, including paired sample analysis, point to specific mutations with potential pathogenetic relevance. RUNX1 mutations predict inferior survival in blast phase MPN, independent of specific treatment strategies.

The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1

Blood ◽  
2013 ◽  
Vol 122 (26) ◽  
pp. 4237-4245 ◽  
Author(s):  
Fathima Zumla Cader ◽  
Martina Vockerodt ◽  
Shikha Bose ◽  
Eszter Nagy ◽  
Marie-Anne Brundler ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cells ◽  
Tyrosine Kinase ◽  
Cell Survival ◽  
Receptor Tyrosine Kinase ◽  
Germinal Center ◽  
Lymphoma Cell ◽  
Lymphoma Cells ◽  
Key Points

Key Points Expression of the EBV oncogene LMP1 in primary human germinal center B cells, upregulates DDR1, a receptor tyrosine kinase activated by collagen Primary HRS cells overexpress DDR1, and its activation significantly increases lymphoma cell survival in vitro

Function of STAT5 Isoforms in Bcr-Abl Positive Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1313-1313
Author(s):  
Michael Schaller-Schoenitz ◽  
Iris Dallmann ◽  
Arnold Ganser ◽  
Michaela Scherr ◽  
Matthias Eder
Keyword(s):  
Cell Proliferation ◽  
Tyrosine Kinase ◽  
Cell Survival ◽  
Tyrosine Phosphorylation ◽  
Therapeutic Intervention ◽  
Kinase Activity ◽  
Differential Sensitivity ◽  
Blue Staining ◽  
Tyrosine Kinase Activity ◽  
Cell Survival And Proliferation

Abstract Abstract 1313 Chronic myeloid leukemia (CML) is caused by expression of the BCR-ABL oncogene product which exerts constitutive tyrosine kinase activity. Specific inhibition of the BCR-ABL tyrosine kinase activity by small tyrosine kinase inhibitors (TKIs) is now well established as initial therapy for newly diagnosed chronic phase CML. However, TKI treatment is not curative in most cases since CML stem cells have been reported to be largely insensitive to this approach and may be not oncogene-addicted. Therefore, additional targets for therapeutic intervention are under investigation to further improve pharmacotherapy for CML. For example, IFNa, inhibition of the transcription factor FOXO3, or that of JAK2 may represent new options for combinatorial therapy among others. To functionally characterize genes involved in BCR-ABL signalling we earlier used gene-specific RNA interference (RNAi) and identified enhanced sensitivity to inhibition of STAT5 in BCR-ABL+ cells (Scherr et al. 2006). STAT5 which comprises two highly conserved isoforms with over 90% sequence homology (Stat5A and Stat5B) is translocated into the nucleus upon tyrosine phosphorylation and di(oligo-)merisation. To further characterize the molecular mechanisms involved in the observed differential sensitivity against anti-STAT5 RNAi we first designed isoform-specific shRNAs targeting either STAT5A or STAT5B individually. TonB cells - a murine IL-3 dependent cell line with doxycycline (dox)-inducible BCR-ABL expression - were lentivirally transduced in the presence of IL-3 before induction of BCR-ABL-expression by addition of dox. Anti STAT5A- and STAT5B-RNAi revealed isoform-specific reduction of STAT5A and STAT5B expression by over 90% as determined by immunoblotting. There is only very modest cross-reactivity with about 5% and 6% reduction of STAT5A and STAT5B protein-expression in the presence of the complementary shRNAs, respectively. Four days after lentiviral transduction cells were further cultivated with IL-3 or switched to BCR-ABL expression by addition of dox, and cell proliferation was determined by Trypan Blue staining and cell counting. In IL-3 cultures, anti-STAT5A and anti-STAT5B shRNAs reduced the cell number by 47% and 36% as compared to control shRNAs whereas in BCR-ABL cultures, RNAi targeting STAT5A and STAT5B reduced the number of viable cells by 43% and 73%, respectively. Cell viability was not affected in IL-3 cultures, but was reduced by 5% and 38% in BCR-ABL cultures by anti-STAT5A and anti-STAT5B RNAi as compared to control shRNA-transduced cells, respectively. To study whether IL-3 can enhance BCR-ABL function, wildtype TonB cells were cultured with IL-3 and dox. Cell proliferation was maximal with IL-3 alone (100%), followed by dox + IL-3 (65%), and dox (20%), respectively, suggesting that BCR-ABL and IL-3 signalling may compete for some overlapping components. Next, we studied hetero- and homodi(oligo)merisation using endogeneous or epitope-tagged STAT5A and STAT5B isoforms over-expressed in TonB cells. STAT5A was precipitated from cellular lysates with anti-STAT5A as well as epitope-specific antibodies and separated by SDS-PAGE. Immunoblotting revealed an inducible heterodi(oligo) merisation of STAT5A:STAT5B complexes by either IL-3 or BCR-ABL containing tyrosine phosphorylated STAT5. In contrast, STAT5A forms constitutive homodimers (or multimers) independent of stimulation (and tyrosine phosphorylation) by IL-3 or BCR-ABL in the presence or absence of imatinib. Finally, cell survival and proliferation was independent of the presence of STAT5A homodimers suggesting that this variant of STAT5 dimers is not functional in TonB cells. In summary, our data suggest unique roles for STAT5A and STAT5B for BCR-ABL mediated cell proliferation and survival in TonB cells. Whereas STAT5A can constitutively homodi(oligo-)merize, STAT5A:STAT5B heterodi(oligo)merisation is inducible, depends on tyrosine phosphorylation and corresponds to cell survival and proliferation. These data suggest the evaluation of STAT5B-specific therapeutic intervention in BCR-ABL expressing cells in preclinical models. Disclosures: No relevant conflicts of interest to declare.

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