A cytosine-rich splice regulatory determinant enforces functional processing of the human {alpha}-globin gene transcript
The establishment of efficient and stable splicing patterns in terminally differentiated cells is critical to maintenance of specific functions throughout the lifespan of an organism. The human α-globin (hα-globin) gene contains 3 exons separated by 2 short introns. Naturally occurring α-thalassemia mutations that trigger aberrant splicing have revealed the presence of cryptic splice sites within the hα-globin gene transcript. How cognate (functional) splice sites are selectively used in lieu of these cryptic sites has remained unexplored. Here we demonstrate that the preferential selection of a cog...
Source: Blood - May 22, 2019 Category: Hematology Authors: Ji, X., Humenik, J., Liebhaber, S. A. Tags: Red Cells, Iron, and Erythropoiesis Source Type: research
Peripheral serotonin causes dengue virus-induced thrombocytopenia through 5HT2 receptors
Dengue virus (DENV) is the most prevalent vector-borne viral pathogen, infecting millions of patients annually. Thrombocytopenia, a reduction in circulating platelet counts, is the most consistent sign of DENV-induced disease, independent of disease severity. However, the mechanisms leading to DENV-induced thrombocytopenia are unknown. Here, we show that thrombocytopenia is caused by serotonin derived from mast cells (MCs), which are immune cells that are present in the perivascular space and are a major peripheral source of serotonin. We show that during DENV infection, MCs release serotonin, which prompts platelet activa...
Source: Blood - May 22, 2019 Category: Hematology Authors: Masri, M. F. B., Mantri, C. K., Rathore, A. P. S., John, A. L. S. Tags: Thrombocytopenia, Phagocytes, Granulocytes, and Myelopoiesis, Platelets and Thrombopoiesis Source Type: research
Myelofibrosis osteoclasts are clonal and functionally impaired
Bone marrow (BM) sclerosis is commonly found in patients with late-stage myelofibrosis (MF). Because osteoclasts (OCs) and osteoblasts play a key role in bone remodeling, and MF monocytes, the OC precursors, are derived from the neoplastic clone, we wondered whether decreased OC numbers or impairment in their osteolytic function affects the development of osteosclerosis. Analysis of BM biopsies from 50 MF patients showed increased numbers of multinucleated tartrate-resistant acid phosphatase (TRAP)/cathepsin K+ OCs expressing phosphorylated Janus kinase 2 (JAK2). Randomly microdissected TRAP+ OCs from 16 MF patients harbor...
Source: Blood - May 22, 2019 Category: Hematology Authors: Veletic, I., Manshouri, T., Multani, A. S., Yin, C. C., Chen, L., Verstovsek, S., Estrov, Z. Tags: Myeloid Neoplasia, Brief Reports Source Type: research
NCAM1 (CD56) promotes leukemogenesis and confers drug resistance in AML
In this study, we investigated the impact of NCAM1 expression on leukemogenesis, drug resistance, and its role as a biomarker to guide therapy. Beside t(8;21) leukemia, NCAM1 expression was found in most molecular AML subgroups at highly heterogeneous expression levels. Using complementary genetic strategies, we demonstrated an essential role of NCAM1 in the regulation of cell survival and stress resistance. Perturbation of NCAM1 induced cell death or differentiation and sensitized leukemic blasts toward genotoxic agents in vitro and in vivo. Furthermore, Ncam1 was highly expressed in leukemic progenitor cells in a murine ...
Source: Blood - May 22, 2019 Category: Hematology Authors: Sasca, D., Szybinski, J., Schüler, A., Shah, V., Heidelberger, J., Haehnel, P. S., Dolnik, A., Kriege, O., Fehr, E.-M., Gebhardt, W. H., Reid, G., Scholl, C., Theobald, M., Bullinger, L., Beli, P., Kindler, T. Tags: Myeloid Neoplasia Source Type: research
Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia
This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34+ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient–derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral ant...
Source: Blood - May 22, 2019 Category: Hematology Authors: Sanchez-Martinez, D., Baroni, M. L., Gutierrez-Agüera, F., Roca-Ho, H., Blanch-Lombarte, O., Gonzalez-Garcia, S., Torrebadell, M., Junca, J., Ramirez-Orellana, M., Velasco-Hernandez, T., Bueno, C., Fuster, J. L., Prado, J. G., Calvo, J., Uzan, B., Tags: Immunobiology and Immunotherapy, Lymphoid Neoplasia, Clinical Trials and Observations Source Type: research
PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell-inflamed phenotype
Programmed death-ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism across a variety of human cancers. A unique genetic mechanism underlying PD-L1 upregulation has been uncovered in classical Hodgkin lymphoma (cHL), in which copy gains of the chromosomal region (9p24.1) containing the programmed death-1 (PD-1) ligands PD-L1 and PD-L2 are recurrently observed. While chromosome 9p24.1 copy-number alterations are ubiquitous in cHL, they also occur in diffuse large B-cell lymphoma (DLBCL), albeit with a lower incidence. Here, fluorescence in situ hybridization was used to identify DLBCLs harbo...
Source: Blood - May 22, 2019 Category: Hematology Authors: Godfrey, J., Tumuluru, S., Bao, R., Leukam, M., Venkataraman, G., Phillip, J., Fitzpatrick, C., McElherne, J., MacNabb, B. W., Orlowski, R., Smith, S. M., Kline, J. Tags: Immunobiology and Immunotherapy, Lymphoid Neoplasia Source Type: research
How I manage anticoagulant therapy in older individuals with atrial fibrillation or venous thromboembolism
Anticoagulant therapy is the most effective strategy to prevent arterial and venous thromboembolism, but treating older individuals is challenging, because increasing age, comorbidities, and polypharmacy increase the risk of both thrombosis and bleeding. Warfarin and non–vitamin K antagonist oral anticoagulants are underused and often underdosed in the prevention of stroke in older patients with atrial fibrillation because of concerns about the risk of bleeding. Poor adherence to anticoagulant therapy is also an issue for older patients with atrial fibrillation and those at risk of recurrent pulmonary embolism. In th...
Source: Blood - May 22, 2019 Category: Hematology Authors: Chan, N. C., Eikelboom, J. W. Tags: How I Treat, Free Research Articles, Thrombosis and Hemostasis Source Type: research
Genetics and mechanisms of NT5C2-driven chemotherapy resistance in relapsed ALL
Mutations in the cytosolic 5' nucleotidase II (NT5C2) gene drive resistance to thiopurine chemotherapy in relapsed acute lymphoblastic leukemia (ALL). Mechanistically, NT5C2 mutant proteins have increased nucleotidase activity as a result of altered activating and autoregulatory switch-off mechanisms. Leukemias with NT5C2 mutations are chemoresistant to 6-mercaptopurine yet show impaired proliferation and self-renewal. Direct targeting of NT5C2 or inhibition of compensatory pathways active in NT5C2 mutant cells may antagonize the emergence of NT5C2 mutant clones driving resistance and relapse in ALL. (Source: Blood)
Source: Blood - May 22, 2019 Category: Hematology Authors: Dieck, C. L., Ferrando, A. Tags: Lymphoid Neoplasia, Blood Spotlight Source Type: research
Editing aberrant splice sites efficiently restores {beta}-globin expression in {beta}-thalassemia
The thalassemias are compelling targets for therapeutic genome editing in part because monoallelic correction of a subset of hematopoietic stem cells (HSCs) would be sufficient for enduring disease amelioration. A primary challenge is the development of efficient repair strategies that are effective in HSCs. Here, we demonstrate that allelic disruption of aberrant splice sites, one of the major classes of thalassemia mutations, is a robust approach to restore gene function. We target the IVS1-110G>A mutation using Cas9 ribonucleoprotein (RNP) and the IVS2-654C>T mutation by Cas12a/Cpf1 RNP in primary CD34+ hematopoie...
Source: Blood - May 22, 2019 Category: Hematology Authors: Xu, S., Luk, K., Yao, Q., Shen, A. H., Zeng, J., Wu, Y., Luo, H.-Y., Brendel, C., Pinello, L., Chui, D. H. K., Wolfe, S. A., Bauer, D. E. Tags: Plenary Papers, Red Cells, Iron, and Erythropoiesis, Brief Reports, Gene Therapy Source Type: research
JAK inhibitors and risk of B-cell lymphomas
(Source: Blood)
Source: Blood - May 22, 2019 Category: Hematology Authors: Rumi, E., Zibellini, S. Tags: Free Research Articles COMMENTS Source Type: research
{alpha}-Globin pre-mRNA splicing, revisited
(Source: Blood)
Source: Blood - May 22, 2019 Category: Hematology Authors: Conboy, J. G. Tags: Free Research Articles COMMENTS Source Type: research
Serotonin, key to thrombocytopenia in dengue?
(Source: Blood)
Source: Blood - May 22, 2019 Category: Hematology Authors: de Mast, Q., de Groot, P. G. Tags: Free Research Articles COMMENTS Source Type: research
NCAM1 supports therapy resistance and LSC function in AML
(Source: Blood)
Source: Blood - May 22, 2019 Category: Hematology Authors: Sykes, S. M. Tags: Free Research Articles COMMENTS Source Type: research
Anti-CD1a CAR T cells to selectively target T-ALL
(Source: Blood)
Source: Blood - May 22, 2019 Category: Hematology Authors: Maciocia, P. M., Pule, M. A. Tags: Free Research Articles COMMENTS Source Type: research
A novel therapeutic strategy for {beta}-thalassemia
(Source: Blood)
Source: Blood - May 22, 2019 Category: Hematology Authors: Townes, T. M. Tags: Free Research Articles COMMENTS Source Type: research
