Targeting Oncoprotein Translation with Rocaglates in MYC-Driven Lymphoma
Background: c-MYC (MYC) is commonly dysregulated in aggressive B cell lymphomas. MYC associated lymphoma, especially Double Hit lymphoma (DHL) and Double-Expression Lymphoma (DEL) which are characterized by MYC and BCL2 dual overexpression usually present with the inferior outcome as rapid disease progression and poor response to standard chemotherapy regimen. Nevertheless, MYC is considered as an "undruggable" target and targeting strategies such as suppressing MYC transcription by bromodomain (BRD)-4 inhibitors have been widely investigated in both preclinical models and clinical trials. However, increasing evidence has ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Zhang, X., Bi, C., Lu, T., Yue, T., Zhang, W., Zhang, X., Cheng, W., Tian, T., Lunning, M. A., Vose, J. M., Pelletier, J., Porco, J. A., Tao, J., Fu, K. Tags: 625. Lymphoma: Pre-Clinical-Chemotherapy and Biologic Agents: Specific Pathway Inhibitors Source Type: research
Enhancer Deregulation in Myeloma
The complexity of gene expression regulation is the result of a composite interplay between promoters, enhancers and other cis-acting regulatory elements bound by transcription factors (TFs) that controls the transcriptional activity of genes. Primary tumor cells, in comparison to their healthy counterparts, are known to display altered enhancer repertoires that are associated with tumor-specific transcription. Large groups of transcriptional enhancers cluster together to form super-enhancers (SEs). These elements have been shown to control genes that are important for maintaining cell identity but are also frequently asso...
Source: Blood - November 21, 2018 Category: Hematology Authors: Neri, P. Tags: Targeting Epigenetic Regulation in Myeloma Source Type: research
Targeted Inhibition of PI3K {alpha}/{delta} Is Synergistic with BCL-2 Blockade in Genetically Defined Subtypes of DLBCL
Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease that is transcriptionally classified into germinal center B-cell (GCB) and activated B-cell (ABC) subtypes. A subset of both GCB- and ABC-DLBCLs are dependent on B-cell receptor (BCR) signaling. Previously, we defined distinct BCR/PI3K-mediated survival pathways and subtype-specific apoptotic mechanisms in BCR-dependent DLBCLs (Cancer Cell 2013 23:826). In BCR-dependent DLBCLs with low baseline NF-B activity (GCB tumors), targeted inhibition or genetic depletion of BCR/PI3K pathway components induced expression of the pro-apoptotic HRK protein. In...
Source: Blood - November 21, 2018 Category: Hematology Authors: Bojarczuk, K., Wienand, K., Ryan, J. A., Chen, L., Villalobos-Ortiz, M., Mandato, E., Stachura, J., Lawton, L. N., Letai, A., Chapuy, B., Shipp, M. A. Tags: 625. Lymphoma: Pre-Clinical-Chemotherapy and Biologic Agents: Specific Pathway Inhibitors Source Type: research
Clinical Application of Epigenetic Modifier Mutations in Myeloma
Epigenetic deregulation is one of the key mechanisms leading to the development of multiple myeloma (MM). While one of the most commonly discussed mechanisms is the deregulation of MMSET by the t(4;14); recent studies have identified a range of other mechanisms that exert important effects and are also potentially amenable to therapy. Methylation patterns are important in MM progression and are characterized by global hypomethylation and gene specific hypermethylation. Interestingly, while this pattern is globally true, the etiologic variants of MM have distinct patterns arguing for their pathologic relevance of acquired m...
Source: Blood - November 21, 2018 Category: Hematology Authors: Morgan, G. J. Tags: Targeting Epigenetic Regulation in Myeloma Source Type: research
A Novel HCK Inhibitor Kin-8193 Blocks BTK Activity in BTKCys481 Mutated Ibrutinib Resistant B-Cell Lymphomas Driven By Mutated MYD88
Activating mutations in MYD88 alone or in coordination with BCR activating mutations transactivate Bruton's tyrosine kinase (BTK) in WM and ABC DLBCL cells (Yang et al, Blood 2013; Wilson WH et al, Nat Med 2015; Phelan JD, Nature 2018). Ibrutinib is a covalent inhibitor that binds to BTKCys481 and is active in MYD88 mutated WM and ABC-DLBCL (Treon et al, NEJM 2015; Wilson et al, Nat Med, 2015). Acquired resistance to ibrutinib is increasingly being recognized in WM, as well as other B-cell malignancies due to somatic mutations at BTKCys481 that abrogate BTK-ibrutinib binding (Xu et al, Blood 2017). BTKCys481 mutations are ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Yang, G., Wang, J., Tan, L., Liu, X., Munshi, M., Chen, J. G., Xu, L., Tsakmaklis, N., Demos, M., Kofides, A., Guerrera, M. L., Chan, G. G., Hunter, Z. R., Patterson, C., Castillo, J. J., Buhrlage, S. J., Gray, N. S., Treon, S. P. Tags: 625. Lymphoma: Pre-Clinical-Chemotherapy and Biologic Agents: Specific Pathway Inhibitors Source Type: research
New Advances Along the Common Coagulation Pathway
Hemostasis is achieved through spatially and temporally regulated thrombin generation following vascular injury. Blood coagulation factor V plays an important role in this process as it has a major impact on thrombin production. FV is a large, heavily glycosylated protein sharing homology and domain organization with FVIII (A1-A2-B-A3-C1-C2). It is an inactive procofactor and must be cleaved by thrombin or other proteases to remove the B-domain to yield activated FV (FVa). FVa is a cofactor for FXa in the prothrombinase complex, the enzyme that activates prothrombin. Given the profound effect FVa has on thrombin formation,...
Source: Blood - November 21, 2018 Category: Hematology Authors: Camire, R. M. Tags: Vascular Biology Components of Hemostasis Source Type: research
The Regulation of Hematopoietic Stem Cells and Erythropoiesis
Hematopoietic stresses mobilize hematopoietic stem cells (HSCs) from the bone marrow to the spleen and induce extramedullary hematopoiesis (EMH), including erythropoiesis. We assessed the sources of the key niche factors, SCF and CXCL12, in the mouse spleen after EMH induction by cyclophosphamide plus granulocyte colony-stimulating factor, blood loss, or pregnancy. In each case, Scf was expressed by endothelial cells and Tcf21+ stromal cells, primarily around sinusoids in the red pulp, while Cxcl12 was expressed by a subset of Tcf21+ stromal cells (Nature 527:466, 2015). EMH induction markedly expanded the Scf-expressing e...
Source: Blood - November 21, 2018 Category: Hematology Authors: Morrison, S. Tags: Blood Building: How to Make a Red Cell Source Type: research
Activating Mutations in CSF1R and Additional Receptor Tyrosine Kinases in Sporadic and Familial Histiocytic Neoplasms
Genomic analyses of histiocytic neoplasms (including Langerhans Cell Histiocytosis (LCH) and the non-LCH Erdheim-Chester Disease (ECD)) have revolutionized our understanding of these disorders as clonal hematopoietic malignancies driven by MAPK signaling and led to FDA approval of vemurafenib for BRAFV600E-mutant ECD. Despite these advances, several questions about the pathogenesis of the histiocytoses remain unanswered. For example, the cell-of-origin of the histiocytoses is not definitively known. In addition, histiocytoses represent a spectrum of diseases, and genetic alterations across histiocytosis subtypes have not b...
Source: Blood - November 21, 2018 Category: Hematology Authors: Durham, B. H., Lopez-Rodrigo, E., Abramson, D. H., Picarsic, J., Pastore, A., Mandelker, D., Walsh, M. F., Arcila, M. E., Ladanyi, M., Solit, D., Berger, M. F., Hyman, D. M., Ki, M., Dunkel, I., Geissmann, F., Diamond, E. L., Abdel-Wahab, O. I. Tags: 635. Myeloproliferative Syndromes: Basic Science: Identification of Novel Therapeutic Targets Source Type: research
JAK2 V617F Dimerizes Homodimeric Cytokine Receptors Cytosolic Domains By Requiring Pseudokinase Domain Residues That Promote JAK2 Dimerization and Oncogenic Activity
JAK2 plays roles in several signaling pathways by binding to multiple distinct cytokine receptors. Dysfunction of JAK2 signaling is associated with hematopoietic malignancies. The acquired mutation JAK2 V617F, which constitutively activates JAK2 kinase, is the most common molecular event associated with myeloproliferative disorders.Using a combination of bioluminescence energy transfer and protein fragment complementation assays we show that V617F located in the pseudokinase domain of JAK2 plays an important role on JAK2 dimerization via the C-terminal kinase domains. Using NanoBRET we show that JAK2 dimerization via the C...
Source: Blood - November 21, 2018 Category: Hematology Authors: Leroy, E., Balligand, T., Constantinescu, S. N. Tags: 635. Myeloproliferative Syndromes: Basic Science: Identification of Novel Therapeutic Targets Source Type: research
Inhibitor of DNA Binding 2 (ID2) Plays a Key Tumor Suppressor Role in Promoting Oncogenic Transformation in Multiple Myeloma
Dysregulation of transcriptional control is a common phenomenon associated with oncogenesis. Inhibitors of DNA binding (ID) proteins are critical actors in lymphopoiesis, acting as regulators of transcription through a helix-loop-helix (HLH) domain which enables heterodimerization with basic HLH (bHLH) proteins inhibiting their binding to DNA. ID proteins have been implicated in malignant transformation, but their role in multiple myeloma (MM) is unknown. Here, we evaluated the role of ID proteins in biology and transcriptional dysregulation in MM.We first evaluated the expression of the four ID proteins in normal and mali...
Source: Blood - November 21, 2018 Category: Hematology Authors: Perini, T., Szalat, R., Samur, M. K., Fulciniti, M., Lopez, M. A., Lawlor, M., Ott, C. J., Li, N., Xu, Y., Wen, K., Amodio, N., Morelli, E., Anderson, K., Ciceri, F., Munshi, N. Tags: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Transcriptome Analysis of Myeloma Cells and Their Immune Microenvironment Source Type: research
The Innate Immune Sensor Sting Regulates Intestinal Inflammation and GVHD after Allogeneic Hematopoietic Stem Cell Transplantation in Knock-out and Human Allele Knock-in Recipient Mice
Graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplants (allo-HSCTs). Pre-HSCT conditioning typically consists of irradiation and drug administration resulting in the death of rapidly dividing cells. Damage to host tissues initiates a cytokine storm, promoting activation and expansion of donor anti-host alloreactive T cells. Cell death following conditioning has promoted the hypothesis that sensors of cytoplasmic DNA damage in GVHD target tissues contribute to cytokine production. We identified a role for Stimulator of Inte...
Source: Blood - November 21, 2018 Category: Hematology Authors: Bader, C. S., Barreras, H., Lightbourn, C. O., Copsel, S., Ahn, J., Barber, G. N., Jin, L., Levy, R. B. Tags: 701. Experimental Transplantation: Basic Biology, Pre-Clinical Models: Gut Reactions in GVHD Source Type: research
ST2 and ROR-{gamma}-t Roles in Intestinal Regulatory T Cells
Allogeneic hematopoietic cell transplantation (allo-HCT) is an essential therapeutic modality for patients with hematological malignancies and benign blood disorders. Unfortunately, acute graft-versus-host disease (aGVHD) remains the major complication of allo-HCT and is associated with high mortality. Soluble STimulation-2 (sST2) is increased during aGVHD while regulatory T cells (Tregs) that express membrane-bound ST2 prevent GVHD through unknown mechanisms. Herein, we studied nonlymphoid tissue ST2+ Tregs in murine models of allo-HCT. Transplantation of Foxp3- T cells and Tregs sorted from different Foxp3 reporter mice ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Yang, J., Ramadan, A., Reichenbach, D., Loschi, M., Zhang, J., Griesenauer, B., Liu, H., Hippen, K. L., Blazar, B. R., Paczesny, S. Tags: 701. Experimental Transplantation: Basic Biology, Pre-Clinical Models: Gut Reactions in GVHD Source Type: research
Prediction of Acute Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation Using a Machine Learning Algorithm
This study was a database dependent retrospective cohort study analyzing the data of adult recipients of HSCT obtained from the registry of Japanese Society for Hematopoietic Cell Transplantation. Pre-HSCT parameters, such as those for patients, donors, conditioning regimens, and other procedures were retrieved from the database and introduced into the data mining approach. The alternating decision tree (ADTree) machine learning algorithm was applied to develop a model. This cohort was randomly divided into the training cohort (70% of the entire dataset) and the validation cohort (the remaining 30%). The algorithm was trai...
Source: Blood - November 21, 2018 Category: Hematology Authors: Arai, Y., Kondo, T., Fuse, K., Shibasaki, Y., Masuko, M., Sugita, J., Teshima, T., Uchida, N., Fukuda, T., Ohashi, K., Ozawa, Y., Ichinohe, T., Kanda, Y., Atsuta, Y. Tags: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: GVHD Grading and Outcomes and Management Source Type: research
Metabolomics Profiling after Allogeneic Hematopoietic Stem Cell Transplantation Unravels a Specific Signature in Human Acute GVHD
This study highlights the potential role of circulating metabolites in GvHD pathophysiology that could be targeted for prophylaxis or treatment.FigureDisclosuresPeffault De Latour: Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding. (Source: Blood)
Source: Blood - November 21, 2018 Category: Hematology Authors: Michonneau, D., Latis, E., Dubouchet, L., Peffault De Latour, R., Robin, M., Sicre De Fontbrune, F., Rogge, L., Socie, G. Tags: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: GVHD Grading and Outcomes and Management Source Type: research
Neutrophil KLF2 Regulates Arterial and Venous Thrombosis
Experimental, clinical and pathological studies support an important link between inflammation and thrombosis. Although accumulating evidence suggests that cells of the innate immune system contribute to the thrombotic process, the identity of nodal molecular determinants operative in immune cells remains poorly understood. Our previous work in mice bearing global deletion of the transcription factor KLF2 identifiedthis factor as a critical mediator of thrombosis). Here, using cell-specific KLF2 deleted murine models (endothelial, platelet, and myeloid- deleted KLF2) we identify myeloid KLF2 as the major determinant of thr...
Source: Blood - November 21, 2018 Category: Hematology Authors: Nayak, L. V., Lapping, S., Maiseyeu, A., Schmaier, A. H., Jain, M. Tags: 301. Vascular Wall Biology, Endothelial Progenitor Cells, and Platelet Adhesion, Activation, and Biochemistry: Vascular Physiology and Thrombosis Source Type: research
