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.

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.


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


Thursday, January 24, 2019

A patient-derived xenograft model for myelodysplastic syndrome (MDS), using cytokine-humanized immunodeficient “MISTRG” mice

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

NSG mouse.jpgMyelodysplastic syndromes (MDS) are a group of disorders of the hematopoietic stem cells that frequently harbor mutations in transcriptional regulators, DNA repair genes and spliceosome factors. Preclinical studies of MDS have been limited due to lack of good cell lines and the difficulty to grow and expand human MDS samples ex vivo or in xenotransplantation models. NSG immunodeficient mice are very useful to expand ALL and AML cells, but have not shown satisfactory results with MDS samples. Over the past years some slight improvements were obtained by using immunodeficient mice that express human cytokines. A new study now reports a novel and efficient MDS xenotransplantation model, using “MISTRG” mice, expressing humanized M-CSF, IL3/GM-CSF, SIRP alpha, and Thrombopoietin from their endogenous murine loci in the Rag−/− IL2Rgamma−/−  genetic background. MISTRG MDS patient-derived xenografts (PDX) were successfully obtained for about half of the cases and reproduced the patients’ dysplastic morphology with multi-lineage representation, including erythro- and megakaryopoiesis. MISTRG MDS-PDX models preserved the genetic complexity of the samples and enabled propagation of the samples via serial transplantation. This possibility to expand human MDS samples while maintaining the genetic complexity, at least in part, is a major step forward to study this disease in more detail and to test new (targeted) therapies in an in vivo setting.

Song Y, Rongvaux A, Taylor A, Jiang T, Tebaldi T, Balasubramanian K, Bagale A, Terzi YK, Gbyli R, Wang X, Fu X, Gao Y, Zhao J, Podoltsev N, Xu M, Neparidze N, Wong E, Torres R, Bruscia EM, Kluger Y, Manz MG, Flavell RA, Halene S. A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies. Nat Commun. 2019;10(1):366. 

Friday, January 11, 2019

Blood and guts: hematopoietic stem and progenitor cells resident within human intestinal allografts potentially mediate immune tolerance.

Michael D. Milsom1,2
1.Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg Germany.
2.Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.

HumanInstestinal_Jan2019.pngIn mammals, the bone marrow is a major site of hematopoiesis, with the vast majority of hematopoietic stem and progenitor cells (HSPCs) residing within the medullary cavities of bones. However, alternative sites of so-called extramedullary hematopoiesis have also been defined, such as the spleen, liver and lung, which likely play distinct biological roles supporting hematopoiesis in diverse scenarios, such as during stress; at specific developmental stages; or in the local production of mature blood cell lineages. In a recently published article in Cell Stem Cell, the group of Megan Sykes has made the surprising finding that functional HSPCs reside within the adult intestine of humans. As well as experimentally characterizing HSPCs isolated from human intestine using experimental approaches such as flow cytometry, molecular analysis and xenotransplantation into immune deficient mice, the authors could demonstrate the functional relevance of these cells by characterizing the sustained production of donor-derived mature peripheral blood cells in patients who received intestinal allografts. Intriguingly, intestinal transplantation appeared to robustly result in the de novo production of circulating T cells that had apparently undergone in vivo selection, and which may play a role in modulating immune tolerance. Donor-derived HSPCs were slowly replaced with recipient HSPCs, presumably seeded from a circulating pool of stem cells. Thus, an unexpected side effect of intestinal transplantation appears to be the establishment of hematopoietic chimerism, which may impact on the outcome of the procedure. Clearly this phenomenon warrants further study in order to ascertain whether it can yield new insight into transplant rejection.

Figure legend:
Multiplex immunohistochemistry staining on an ileum specimen collected from a transplant patient 1606 day after intestinal transplantation. The image suggests that human intestinal HSPCs (CD45+ cyan; CD34+ red; and CD90+ yellow) reside in the lamina propria layer of the gut mucosa around the crypts (DAPI in blue). Given that flow cytometric analysis on the ileum specimen collected on the same day showed that all CD45+ cells in the ileum graft were recipient HLA+, the representative HSPC (white arrow) is a recipient-derived HSPC, which presumably populated the donor graft from a circulating pool. Image kindly provided by Megan Sykes, Columbia University, New York.

Fu J., et al., Human Intestinal Allografts Contain Functional Hematopoietic Stem and Progenitor Cells that are Maintained by a Circulating Pool, Cell Stem Cell, DOI: https://doi.org/10.1016/j.stem.2018.11.007

Monday, January 7, 2019

Fighting sterile inflammation in sickle cell disease

Francesca Vinchi, PhD
Lindsley F. Kimball Research Institute (LFKRI), New York Blood Center - NYBC, New York, USA.

Sickle cell disease (SCD) patients carry activated platelets. Given the crucial role of platelets in vascular inflammation and thrombosis, their exacerbated activation might contribute to acute pain crisis and acute chest syndrome in SCD. Platelets express the pattern recognition receptor nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) and Bruton tyrosine kinase (BTK), which regulate inflammosome activation through caspase-1 and IL-1ß cleavage (Figure 1). Inflammosome complex formation eventually results in platelet aggregation and thrombus generation. Recently, Vogel and co-workers showed that caspase-1 and NLRP3 inflammosome activation are increased in circulating platelets isolated from SCD patients as well as SCD mice, and are further aggravated during SCD pain crises. SCD platelet-free plasma stimulation was sufficient to induce inflammosome and caspase-1 activation in platelets from healthy subjects. The authors identified HMGB1-mediated TLR4 (Toll-like receptor 4) signaling induction as the underlying molecular mechanism triggering inflammosome activation in SCD patients. The application of inhibitors of HMGB1, TLR4, BTK or NLRP3 efficiently prevented caspase-1 activation in SCD plasma-treated platelets in vitro and in SCD animals (Figure 1). As a result, platelet aggregation in SCD mice was restored to levels comparable to control mice. Interestingly, the strongest inhibitory effect was achieved via combined therapy with multiple inhibitors. The observation of increased SCD platelet inflammosome activation and pathway identification unravel a novel druggable mechanism to reduce chronic vascular inflammation and abnormal coagulation in SCD. Despite the importance of inflammosome in infection response, its temporary inhibition in this patient population is likely beneficial to counteract platelet aggregation and vasculopathy. Finally, inflammosome inhibition might be effective in other cell types where this mechanism is active (e.g. macrophages), further contributing to an overall reduction of the so called ‘sterile’ inflammation that underlies SCD pathophysiology.

Figure 1. Platelet inflammosome activation drives vascular inflammation and thrombus formation in SCD. HMGB-1-mediated TLR4 pathway activation triggers inflammosome complex formation, caspase-1 activation and IL-1ß cleavage in platelets. Red symbols indicate inhibitors that can be applied to block the pathway and prevent platelet activation for therapeutic purposes in SCD. 

Sebastian Vogel, Taruna Arora, Xunde Wang, Laurel Mendelsohn, James Nichols, Darlene Allen, Arun S. Shet, Christian A.Combs, Zenaide M.N. Quezado, Swee Lay Thein. The platelet NLRP3 inflammosome is upregulated in sickle cell disease via HMGB1/TLR4 and Bruton tyrosine kinase. Blood Advances 2018. 2:2672-2680.