HemaBites

HemaBites showcase hematology news and short commentaries on recent high-impact articles published in international journals. This blog will keep you up to date with the latest developments and discoveries in the field of hematology.

Thursday, May 16, 2019

​Inflammasome-triggered pyroptosis: a new driver of intravascular coagulation

Francesca Vinchi

Iron Research Program, Lindsley Kimball Research Institute, New York Blood Center, New York, New York.


Disseminated intravascular coagulation (DIC) is a pathologic state of systemic activation of blood coagulation which often characterizes sepsis and leads to vessel occlusion, organ injury and eventually death. Tissue factor (TF) plays a key initiating role in DIC. Recently, Wu and coworkers unraveled the molecular mechanisms linking bacterial infection to TF-induced coagulation cascade. The authors showed that macrophage inflammasome activation by bacterial proteins and LPS induces TF release and systemic blood clotting with consequent massive tissue thrombosis. Activated inflammatory caspases 1 and 11, by cleaving gasdermin D (GSDMD), trigger the formation of pores in the plasma membrane which promote IL-1b/IL-18 release and pyroptosis, a lytic form of cell death hallmarked by membrane rupture. The authors showed that animals deficient for caspase 1/11 and GSDMD are protected from DIC-induced lethality and do not develop intravascular coagulation and tissue fibrin deposition, demonstrating a key role of inflammasome and pyroptosis in DIC. Whereas the release of IL-1b and IL-18 downstream inflammasome activation is not needed, inflammasome-induced pyroptosis and the consequent release of microvescicles containing TF are required to initiate blood clotting and lead to DIC. Clodronate-mediated depletion of monocytes and macrophages prevents inflammasome-induced coagulation and lethality, indicating that pyroptosis of these cell types is a major driver of coagulation. This mechanism is dependent on TF release, as genetic and pharmacological inhibition of TF abolishes inflammasome-mediated blood clotting and protects against death. Overall this work identifies inflammasome activation and pyroptosis as molecular mechanisms leading to TF-induced DIC and suggests that this pathway is a potential therapeutic target to prevent sepsis-related intravascular coagulation.

Reference:

Wu C, Lu W, Zhang Y et al. Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis. Immunity 2019; 50, 1-11.

Figure: Model of coagulation triggered by inflammasome activation

Inflammasome activation (caspase 1/11) by bacterial products results in GSDMD cleavage followed by GSDMD-dependent macrophage pyroptosis. The pyroptotic process promotes the release of microvescicles containing TF into the circulation, which in turn triggers blood coagulation, leading to organ damage and eventually death.


Friday, April 12, 2019

New learning platform for hematology professionals: EHA Campus

Wietske Hollegien, Naomi van Hattem and Manon Saris, European Hematology Assocation, The Hague, The Netherlands

EHA Campus Header.pngOn January 31st the European Hematology Association launched the EHA Campus. Focusing entirely on interactive learning, this new platform offers many tools based on, high quality content on a wide variety of topics, representing all topics of the European Hematology Curriculum.1

Online education enables people to learn in their own time, on their own device, everywhere around the world. EHA finds it very important to offer this possibility to the hematology community, supporting all those who want to update their knowledge.

On EHA Campus, medical and scientific professionals with an interest in hematology can find different types of courses. Most of these include self-assessment opportunities, to test what was learned directly. Current courses range from Morphology quizzes and e-courses to a Statistics course for Clinical Researchers. 

The learning program will be developing along the way: new learning materials will be uploaded regularly. EHA will launch clinical cases, e-courses and morphology cases every month and more courses for clinical researchers are in the pipeline. 
To ensure high quality resources and make sure material is original, up-to-date and relevant, all learning tools are reviewed by designated hematology professionals. 

Access to most courses will be a member-benefit, certificates can be obtained, and courses will be EBAH accredited. 

Visit our platform at ehacampus.ehaweb.org

Reference 
1. Almeida, A, Ar, C, Hellström-Lindberg, E, et al. The European Hematology Curriculum: An Electronic Passport Promoting Professional Competence and Mobility. Hemasphere, June 2018, Volume 2 - Issue 3 - p e49



Monday, April 8, 2019

Targeting RNA splicing in hematological malignancies

Jan Cools, VIB-KU Leuven Center for Cancer Biology, Editor-in-chief HemaSphere

Mutations in pre-mRNA splicing factors and RNA binding proteins are found in various hematological malignancies and include mutations in SF3B1, SRSF2, U2AF1 and ZRSR2. These mutations lead to changes in the splicing of many transcripts and may lead to inactivation of tumor suppressor genes or other changes that favour oncogenesis. An example of this is the alternative splicing of EZH2 in cells with SRSF2 mutation, which leads to downregulation of the EZH2 protein.1 Similarly, Sf3b1 mutation leads to disruption of pre-mRNA splicing and induces senescence in B-cells, but a combination of Sf3b1 mutation with inactivation of Atm leads to increased genomic instability and the development of a CLL-like disease in mice.2 In addition to the splicing factors, also other RNA binding proteins play important roles in myeloid neoplasms. RBM39 was identified as a key RNA binding protein in AML and pharmacological inactivation of RBM39 by indisulam causes aberrant pre-mRNA splicing.3 Many leukemia cell lines were found to be sensitive to this drug, in particular cell lines with mutations in splice factors.3,4 In contrast to RBM39, which is an essential RNA binding protein, RBM25 was identified as a tumor suppressor gene in AML.5 Downregulation of RBM25 promoted the proliferation and decreased cell death in AML cell lines. Mechanistically, this could be linked to the effect on splicing of key transcripts, including the anti-apoptotic BCL2L1 (also known as BCL-X) and the MYC inhibitor BIN1.5 Moreover, in human AML patients low RBM25 levels were associated with high MYC activity and poor outcome. Interestingly, also a number of kinases are implicated in the regulation of splicing and a kinase inhibitor targeting the kinase SRPK1 was recently shown to affect cell cycle and leukemic cell differentiation.6 mRNA analysis demonstrated that SRPK1 inhibition leads to altered isoform levels of important genes implicated in leukemogenesis such as MYB, BRD4 and MED24. Together, these studies provide a better understanding of splicing defects and splicing requirements in normal and malignant hematopoietic cells and open new avenues for targeted therapy.


References

1. Kim E, et al. SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition. Cancer Cell. 2015;27(5):617-30. 

2. Yin S, et al. A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion. Cancer Cell. 2019;35(2):283-296.e5. 

3. Han T, et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science. 2017;356(6336). 

4. Wang E, et al. Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia. Cancer Cell. 2019;35(3):369-384.e7. 

5. Ge Y, et al. The splicing factor RBM25 controls MYC activity in acute myeloid leukemia. Nat Commun. 2019;10(1):172.  

6. Tzelepis K, et al. SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4. Nat Commun. 2018;9(1):5378.

 


Tuesday, March 5, 2019

In memoriam: Prof Francesco Lo Coco

Pieter Sonneveld
European Hematology Association President

Prof Le Coco_web-awards2018-light.jpgOn Sunday, March 3, Prof Francesco Lo Coco, outstanding hematologist, friend and a great man of dialogue, suddenly passed away. This event has struck the hematology community with intense grief.

Francesco Lo Coco is known for his work in Acute Myeloid Leukemia (AML). He is one of the leaders who successfully initiated the treatment of Acute Promyelocytic Leukemia (APL) patients with arsenic trioxide combined with retinoic acid. He has published over 400 original articles in peer-reviewed international journals. His field of work has significantly contributed to improve patient outcome and provided several important concepts with general implications in the therapy of leukemia and cancer.

Francesco Lo Coco served in several scientific societies and research organizations such as the Italian Society of Experimental Hematology (President, 2000-2002), the Italian Ministry of Health (2001-2003), the American Society of Hematology (various functions, 2008-2015), Fondazione Veronesi (2012-2015), the Associazone Italiana Contro le Leucemie-Linfomi e Mieloma (AIL) and the Associazione Italiana per la Ricerca sul Cancro (AIRC). He also served on the Editorial Boards of the Journal of Clinical Oncology (2010-2013), Leukemia (1996-2013) and Haematologica (1994-2018).  

For the European Hematology Association, Francesco Lo Coco was Chairman of the Education Committee from 2008 to 2013. Over the years he contributed to many activities of the Association, participated in many meetings and his colleagues at EHA got to know him as an active and warm personality. Last year, he was granted the EHA José Carreras award for his outstanding contributions to the research and treatment of acute myeloid leukemia (AML). 

The José Carreras Award is only one of the distinctions he received throughout his impressive career. He  also received  the International Prize G. Di Guglielmo, awarded by the Accademia Nazionale dei Lincei (1992), the Commendatore al Merito della Repubblica Italiana (2013), the Sapio Award for Italian Research (Health section, 2014), the Tata Memorial Center Oration, Mumbay, India (2015), the G. Venosta Prize, AIRC (2016) and the P. Stryckmans Memorial Lecture (Belgian Society of Hematology, 2017).

Image legend

Prof Francesco Lo Coco received the Jose Carreras Award 2018 from Prof Pieter Sonneveld, EHA President at EHA23 in Stockholm, Sweden

Friday, February 22, 2019

Turning foes into friends

Melania Tesio
Laboratory of onco-hematology, Institut Necker des Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, Paris, France


Acute myeloid leukemia (AML) is an aggressive hematological cancer in which malignant myeloid cells accumulate in the bone marrow. This disease is driven by multiple genetic abnormalities, such as mutations in the nucleophosmin 1 gene (NPM1), which codes for a protein involved in DNA replication. Found in 30-35% of AML cases, NPM1 mutations are insertional and generate a C-terminal alternative reading frame. In turn, this results in the production of a longer mutant protein, which is endowed with a unique C-terminus. 

A new study now reports that the mutated domain can be exploited for immunotherapy. By analyzing the HLA class I ligandome of 12 primary AMLs, Dyantha van der Lee and colleagues identified a mutant C-terminus-derived peptide (CLAVEEVSL) and demonstrated it to be a targetable neoantigen. T-cells recognizing this peptide, isolated and expanded from peripheral blood mononuclear cells of healthy individuals, showed reactivity against NPM1-mutant AML cells.  Furthermore, the transduction of T-cells with a TCR recognizing the mutant antigen enabled them to strongly and selectively lyse NPM1 mutant primary AML cells but not NPM1-wildtype AML cells. Efficient cytotoxic activity was also observed in-vivo, as the transduced T-cells efficiently killed NPM1 mutant AML cells xenografted into immunodeficient mice. These findings are intriguing and warrant further investigation, for instance in the context of CAR T-cells based immunotherapy.

Figure legend

T-cells recognizing the mutant NPM1 C-terminus-derived peptide CLAVEEVSL show cytotoxic activity against NPM1-mutant AML cells.

Reference

van der Lee DI, Reijmers RM, Honders MW, Hagedoorn RS, de Jong RC, Kester MG, et al. Mutated nucleophosmin 1 as immunotherapy target in acute myeloid leukemia. J Clin Invest2019; 129(2): 774