A cancer mystery of more than forty years ago is solved thanks to Epigenetics

Before the first oncogene mutations were discovered in human cancer in the early 1980s, the 1970s provided the first data suggesting alterations in the genetic material of tumors. In this context, the prestigious magazine “Nature” published in 1975 the existence of a specific alteration in the transformed cell: an RNA responsible for carrying an amino acid to build proteins (transfer RNA) was missing a piece, the enigmatic nucleotide “Y”.

  • Cancer epigenetics group, led by Dr Manel Esteller.

After that outstanding observation, the most absolute silence and ignorance has reigned for forty-five years on the causes and consequences of not having that correct base in that RNA.

In an article that was just published in the Proceedings of the National Academy of Sciences (PNAS) by the group of Dr. Manel Esteller, Director of the Josep Carreras Leukaemia Research Institute, ICREA Research Professor and Professor of Genetics at the University of Barcelona solves this mystery by describing that in cancer cells the protein that generates the nucleotide “Y” is epigenetically inactivated, causing small but highly aggressive tumors.

«Since the original discovery in 1975, there has been much biochemical work to characterize the enzymes involved in the different steps that lead to the desired nucleotide “Y”, a hypermodified guanine, but without connecting this characterization with its defect in tumor biology. We have built the bridge between these two worlds by demonstrating that the epigenetic silencing of the TYW2 gene is the cause of the loss of the elusive nucleotide “Y”», explains Dr. Esteller about the article in the PNAS journal and adds «Epigenetic blockade TYW2 gene occurs mainly in colon, stomach and uterine cancer. And it has undesirable consequences for healthy cells: the postman (RNA) that sends the signal to produce the bricks of our body (proteins) begins to accumulate errors and the cell takes on a different appearance, far from the normal epithelium, which we call mesenchymal and which it is associated with the appearance of metastasis. In this regard, when we study patients with colon cancer in early stages, the epigenetic defect of TYW2 and the loss of the nucleotide “Y” is associated with those tumors that, although small in size, already lead to less survival of the person. We would like to explore now how to restore the activity of the TYW2 gene and restore the longed-for “Y” piece in cancer in order to close the cycle of this story that began so brilliantly in 1975, at the dawn of modern molecular biology», concludes the researcher.

Identified gene mutations impact on the severity of a type of hematologic cancer

►Researchers at the Josep Carreras Leukaemia Research Institute participate in an international study that confirms for the first time that mutation of the two TP53 gene’s copies is associated with a worse prognosis in myelodysplastic syndromes, a group of blood cancers a more frequent in elderly population.

►The results of this study have been published in Nature Medicine journal and represent an advance in the diagnosis and treatment of this type of hematological cancer.

►This is a pioneering result obtained in patients with myelodysplastic syndrome and hopefully these findings can be confirmed in other types of cancer.

The Myelodysplastic Syndromes Group of Josep Carreras Leukaemia Research Institute, led by Dr. Francesc Solé, has participated in the first international study that confirms that having two mutated copies of the TP53 gene, as opposed to a single mutated copy, is associated with a worse prognosis in patients diagnosed with myelodysplastic syndrome (MDS).

This study, published in the prestigious scientific journal Nature Medicine, has been conducted by researchers from the Memorial Sloan Kettering in the USA, involving 25 research centers in 12 countries and has been supervised by the international working group for the prognosis of MDS, whose aim is to develop new international guidelines for the diagnosis and treatment of this disease. This is a preliminary result in order to define a prognostic score based on molecular changes.

Considered the “guardian of the genome,” TP53 is the most commonly mutated gene in cancer. The normal function of TP53 is to detect DNA damages and prevent cells from passing this damage to daughter cells. When TP53 is mutated, the protein resulting from this gene (called p53) can no longer perform this protective function and a cancer may be the result. In most cancers, TP53 mutations are associated with a worse prognosis, such as disease relapse, poor response to treatments and shorter survival.

TP53 exists in duplicate in each of our cells, just like all other genes: one copy from our mother and one copy from our father. Until now, it was not clear whether a mutation of a single copy of TP53 was enough to cause a worse prognosis of the disease, or whether mutations in both copies were necessary.

This study has confirmed for the first time that having the two mutated copies of the TP53 gene is associated with worse results for myelodysplastic syndromes (MDS), a group of blood cancers whose common characteristic is that the stem cells in the bone marrow, in charge of manufacturing all the blood cells, have a defect that makes them produce abnormal cells, unable to perform their usual functions, and in a lower quantity.

  • Grup SMD

    Myelodysplastic Syndromes Research Group from Josep Carreras Leukaemia Research Institute

Dr. Solé, leader of the Josep Carreras Institute’s Myelodysplastic Syndromes group, member of the Spanish Myelodysplastic Syndromes Group (GESMD) and member of the international working group for the prognosis of MDS, explains: “From the Josep Carreras Institute we have actively participated by providing more than a hundred samples from patients with the diagnosis of MDS, in the comparative analysis of cytogenetic (karyotype) results versus those obtained by mass sequencing, and in the final discussion of the findings obtained. The results of this study will allow a great advance in the diagnosis and treatment of myelodysplastic syndromes.Current guidelines do not consider genomic data, such as the mutational status of TP53 and other genes to assess prognosis in patients with MDS or to determine appropriate treatment for this disease. However, studies like this show that we should include this information to improve the diagnosis and treatment of patients”.

By using new computational methods in a serie of 4,444 patients with MDS, the researchers found that a third of the patients with TP53 mutations had only a mutated copy of this gene. These patients had similar results to patients who did not have a TP53 mutation, that is to say good response to treatment, low rates of disease progression and long-term survival. However, two-thirds of patients had both mutated copies of TP53 and these patients had worse results, including resistance to treatment, rapid disease progression, and short-term survival.

In fact, the researchers found that the TP53 mutation status (0, 1, or 2 mutated copies of the gene), was the most important variable in predicting the clinical course of the disease. Given the frequency of TP53 mutations in cancer, these results also advocate to examine the impact of one or two mutations on other types of cancer, both hematologic and solid tumors, and reveal the need of clinical trials specifically designed with these molecular differences.

Identified a new regulatory mechanism of response to metabolic stress that may be relevant for the treatment of leukemia

►Researchers at the Josep Carreras Leukaemia Research Institute have identified a new mechanism for the regulation of the response to metabolic stress that opens the door to new therapeutic targets in the treatment of leukaemia and other malignant haemopathies.

  • Grup Biologia Cromatina

    Chromatin Biology Group

Chromatin Biology group aims to define the mechanisms involved in the cellular response to different types of stress such as metabolic, oxidative and genotoxic stress. In particular, they focus their studies on the impact of a family of enzymes, Sirtuins (responsible of the cellular stress response) in the maintenance of genome stability under these conditions and their impact in aging and different types of cancers, with a special focus on hematologic malignancies.

Dr. Vaquero’s group has just published a multidisciplinary study at Science Advances journal in which they have identified and characterized a new enzymatic activity of the Sirtuin SIRT7 that provides new evidence to understand its regulatory capacity in the cellular response to different types of stress damaging cellular integrity.

The regulation of this response acquires special relevance since these types of stress can produce alterations in the DNA and instability at cell’s energy flow, and are directly involved in the appearance of pathologies such as cancer, neurodegenerative diseases or a number of endocrine pathologies.

The regulatory mechanism identified may represent an important advance towards new therapeutic targets in the treatment of cancer, particularly in hematological cancers, since previous studies have shown that both genome instability and metabolic stress contribute significantly to the development of leukemias and lymphomas.

Other groups have also collaborated In this study, whose first author is Dr. Nicolas Simonet,  including the research groups led by Dr. Manel Esteller and Dr. Marcus Buschbeck (both from the Josep Carreras Leukaemia Research Institute),the Proteomics Unit of this Institute, led by Dr. Carolina de la Torre, as well as groups from Pompeu Fabra University, the Centre for Genomic Regulation, Rutgers  University (USA) and the Max Plank Institute (Germany).

This research has been funded by the Ministry of Economy and Competitiveness, the Agency for the Management of University and Research Grants (AGAUR) of the Government of Catalonia and co-financed by FEDER funds.

Dr. Manel Esteller awarded the Narcís Monturiol Medal for scientific and technological merit from the Government of Catalonia

►The researcher Manel Esteller, director of the Josep Carreras Leukaemia Research Institute, and leader in Cancer Epigenetics, has been awarded the Narcís Monturiol Medal for scientific and technological merit from the Government of Catalonia.

  • Dr. Manel Esteller

Manel Esteller, Director of the Josep Carreras Leukaemia Research Institute, ICREA Research Professor and Chairman of Genetics at the School of Medicine of the University of Barcelona has been awarded the Narcís Monturiol Medal of the Generalitat of Catalonia to the scientific and technological merit, These awards, given since 1982, distinguish individuals and entities for their outstanding contribution to the development of science and technology in Catalonia.

Dr. Manel Esteller graduated in Medicine from the University of Barcelona and received his doctorate with a specialization in molecular genetics of endometrial carcinoma from the same University. He was a postdoctoral researcher and associate at the Johns Hopkins University School of Medicine (Baltimore, USA), where he studied DNA methylation and its relationship to cancer. He led the Cancer Epigenetics Laboratory of the Spanish National Cancer Centre (CNIO) in Madrid and returned to Catalonia in 2008 to direct the Cancer Epigenetics and Biology Program (PEBC) of the Bellvitge biomedical campus. Since 2019 he is the Director of the Josep Carreras Leukaemia Research Institute (IJC) within the framework of the Catalan Research Centers (CERCA). Dr. Esteller’s research has allowed to understand the contribution of epigenetic alterations in human disorders, especially cancer, and to develop biomarkers for the disease, as well as new breakthrough therapies.

The Josep Carreras Institute creates a spin-off to develop therapies for leukaemia based on CAR–T

► This spin-off, called OneChain Immunotherapeutics (OCI), was founded by the Josep Carreras Leukaemia Research Institute, ICREA, and Dr. Pablo Menéndez in Barcelona in June 2020.

► Invivo Ventures, CDTI-Innvierte (Ministry of Industry) and the Josep Carreras Foundation have established a first round of funding of €3,050,000.

► OCI’s aim is to develop treatments based on immunotherapy for malignant blood diseases on the basis of the research results of the group, led by Dr. Pablo Menéndez, ICREA research professor and a researcher at the Josep Carreras Leukaemia Research Institute.

► OCI will carry out three projects, the most advanced of which is a CAR-T CD1a (OCI-1) project for the treatment of cortical T-cell acute lymphoblastic leukemia (coT-ALL), a subtype of leukaemia that mainly affects children and which has a poor prognosis if patients do not respond to standard treatments.

The Josep Carreras Leukaemia Research Institute, a public centre pertaining to the Generalitat de Catalunya’s (Government of Catalonia) CERCA network, has created the OneChain Immunotherapeutics (OCI) spin-off, the aim of which is to develop new immuno-oncological therapeutic tools with various preclinical candidates, based on CAR–T technology for different tumours, such as cortical T-cell acute lymphoblastic leukemia (coT-ALL), a rare subtype of leukaemia that mainly affects children, and which has a poor prognosis.

The spin-off is being funded initially through a round of seed capital, amounting to €3,050,000, provided by Invivo Ventures, the Ministry of Industry, through CDTI-Innvierte, and the Josep Carreras Foundation, and it clearly makes the case for bringing the research carried out by Dr. Pablo Menéndez’s group closer to patients. Dr. Mendez is an ICREA research professor and the scientific director at the Josep Carreras Leukaemia Research Institute’s Hospital Clínic-UB Campus.

Dr. Menéndez, founder of OCI and world renowned for his work in the field of childhood leukaemia, directs the Josep Carreras Institute’s stem cell biology, leukaemia development and immunotherapy group. More than 180 of his studies have been published by the world’s most prestigious scientific journals and, outstanding in his wide-ranging professional career is having been awarded the triennial ED Thomas Postdoctoral Fellowship grant, awarded by the Josep Carreras Foundation in 2006, as well as three grants awarded by the European Research Council (ERC), the most important scientific funding organisation in Europe.

Dr. Menéndez’s group was the first in the world to develop and validate a CD1a specific CAR-T for coT-ALL. The study, published in the journal Blood, has so far been conducted with animal models using both cell lines and primary blasts derived from patients with coT-ALL. Preliminary results show that these CAR-T cells persist in vivo over the long term and retain their anti-leukaemia activity.

The creation of this spin-off marks a further step towards developing adoptive cell immunotherapy, such as CAR–T cell therapy, a treatment that consists of extracting a patient’s T cells (the ones that defend the organism), modifying them in the laboratory, and returning them to the patient. The modification enables the cells to attack the receptors that are located in the membranes of tumour cells (called CD antigens) and eliminate them. With this technique it is the patient’s own modified cells that that attack the cancer cells, and they do so in a directed way, without damaging other, healthy, cells. The funding achieved through this first round is essential for turning research results into products that reach patients because, before they can be used clinically, they must pass safety, efficacy and production process scale tests, and these are technically highly complex and very expensive.

  • From left to right, in front, Evarist Feliu (Josep Carreras Foundation), Luis Pareras (Invivo), Pablo Menéndez (OneChain); standing, Emilià Pola (ICREA) and Albert Ferrer (Invivo).

Dr. Menéndez says, “OCI is the vehicle that will enable us to take all the work we have been doing over all these years and apply it to clinical use. At the academic level it is very complicated to develop these strategies and manage all the regulatory mechanisms associated with the development of a product. OCI will enable us to carry out all the necessary steps so that all our knowledge can be available to patients”.

Antoni García Prat, The Josep Carreras Foundation’s administrator, says “The Foundation is participating in the initial investment by Invivo Ventures and CDTI in support of translational research and also in support of the foundational team. It should be borne in mind that the projects are directed towards rare or childhood blood diseases, or others with few therapeutic alternatives, and that, should the Foundation benefit financially, the proceeds will be entirely invested in the fight against leukaemia, always to the benefit of patients”.

Prof. Evarist Feliu, president of the Josep Carreras Leukaemia Research Institute’s Delegate Committee, says, “At the present time immunotherapy constitutes a wide and hopeful field for cancer treatment. Its major clinical interest is currently focussed on immune system checkpoint inhibitors and adoptive therapy strategies with T cells, with more than 700 clinical trials taking place throughout the world for the treatment of malignant blood diseases and, to a lesser extent, solid tumours”.

Jorge Alemany, CEO of OneChain, adds, “OneChain is a perfect example of Public Private Partnership (PPP) for the benefit of patients. A representative of the voluntary sector (FJC) promotes a project thanks to the support of the public sector (ICREA and CDTI) and private effort (Invivo)”.

Dr. Lluís Pareras and Albert Ferrer, founding partners of Invivo Ventures, say, “We are joining forces with the Josep Carreras Foundation and the Josep Carreras Institute to develop a CAR-T platform with potential for the clinical application of solutions for devastating blood diseases. This platform, led by Dr. Pablo Menéndez, includes the CAR-T CD1a programmes, as well as two other platforms, which we can not disclose at the moment, but which we hope will be able to significantly improve the lives of many cancer patients”.

 

ADDITIONAL INFORMATION

Thymic cortical T-cell acute lymphoblastic leukemia

More than 350 children are diagnosed with leukaemia every year in our country. Leukaemia accounts for around a third of childhood neoplasias.

Childhood leukaemia is an aggressive kind of blood cancer. The affected cells can be of the lymphoid or myeloid lineage. The most usual kind of leukaemia in children is of lymphoid origin, the most common kind being acute lymphoblastic leukaemia (ALL), which accounts for approximately 80% of childhood cases.

Acute lymphoblastic leukaemia in turn can originate in B or T lymphocytes. 80% of childhood acute lymphoblastic leukaemias are B type.

8 of every 10 children manage to overcome the disease. In the case of T-type ALL fewer than 100 cases are diagnosed every year in Spain and these are “subdivided” into four main kinds by means of immunophenotyping studies: Pro-T, Pre-T, thymic cortical and thymic mature.

Cortical T-cell acute lymphoblastic leukemia (coT-ALL) accounts for 40% of T-type acute leukaemias. Fewer than 30 children are diagnosed with this every year in our country. Usually they are adolescents between the ages of 11 and 17. A third of them do not respond to existing therapies and we can not offer them any further opportunities with the current arsenal of therapies.

About Dr. Pablo Menéndez

Dr. Menéndez was born in Avilés, Asturias, in 1974. He graduated in biochemistry from the University of Salamanca (1997) and as a Doctor of Medicine (Hematology) from the same university in 2002, under the supervision of Prof. Alberto Orfao and Prof. Jesús San Miguel. He carried out his postdoctoral training in stem cell biology at the Mick Bhatia laboratory in Canada from 2003 to 2005, and in childhood leukaemia at the laboratory of de Mel Greaves in London from 2005 to 2007. In 2007 he was appointed director of the Stem Cell Bank of Andalusia and directed his own laboratory at the Biomedical research Centre in Granada until July 2011, when he commenced work as a lead researcher at the Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO). In June 2013 he was appointed ICREA Research Professor and Research Director of the Josep Carreras Leukaemia Research Institute’s Hospital Clínic-UB Campus.

About the Josep Carreras Foundation

The Josep Carreras Leukaemia Foundation was established in 1988 with the intention of contributing to finding a definitive cure for this disease. Its efforts are concentrated on four basic areas: administering the Spanish Bone Marrow Donor Registry (REDMO), scientific research, carried out by the Josep Carreras Leukaemia Research Institute, patient guidance through an online patient consultation channel, and reception apartments for patients who need to undergo treatment and have to spend a long time far from home.

About the Josep Carreras Leukaemia Research Institute

The Josep Carreras Leukaemia Research Institute, a public centre pertaining to the Generalitat de Catalunya’s CERCA network, was established in 2010 with the aim of furthering biomedical research and personalised medicine in the field of leukaemia and other onco-hematological diseases. It is the first research centre in Europe exclusively focussed on leukaemia and malignant blood diseases, and one of the very few in the world. The Josep Carreras Institutes has three coordinated but independent scientific campuses: University of Barcelona Hospital Clínic Campus, The Catalan Institute of Oncology/Germans Trias i Pujol Campus, and the Sant Pau – Autonomous University of Barcelona (UAB) Campus.

About ICREA

ICREA, Catalan Institution for Research and Advanced Studies, is a foundation funded by the Catalan Government. ICREA was established in response to the need for new contracting formulas that would make it possible to compete on a level playing field with other research systems, with a view to contracting outstanding and highly-talented academic and scientific staff. ICREA is an open institution. It works shoulder to shoulder with Catalan universities and research centres to integrate ICREA researchers into the Catalan research system. ICREA offers researchers from around the world permanent posts to come and conduct research in Catalonia. Over the years it has become synonymous with academic excellence around the world. ICREA has researchers in all fields of knowledge who carry out their research work in 48 universities and research institutions in Catalonia.

About CDTI

The Centre for Industrial Technological Development (CDTI) is an organ of the General State Administration that supports knowledge-based innovation. It provided guidance and public funding by means of grants and partially reimbursed funds. The CDTI also internationally projects business R&D projects and innovation for companies and Spanish organisations. It manages Spanish participation in international R&D&I organisms, such as Horizonte2020 and Eureka, and in the Science and Space industries. Furthermore, through the Innvierte Economía Sostenible initiative, it supports and facilitates the capitalisation of technological companies.

About Invivo Ventures

Invivo Ventures FCR invests in life-science companies at an early stage and is administered by Invivo Capital Partners, an administrative company founded by Dr. Lluís Pareras and Albert Ferrer. Both administrators have wide experience in the sector and also administer the risk capital company, Healthequity SCR. Invivo Ventures FCR has a majority of private investors with the support of a number of institutional investors such as, the European Investment Fund (EIF), Fond-ICO Global, the Institut Català de Finances and the Institut Valencià de Finances.

Un nuevo nanofármaco bloquea las células tumorales de la leucemia mieloide aguda sin dañar las sanas

►La nanopartícula, creada por investigadores del CIBER-BBN, se dirige únicamente a las células leucémicas, lo que reduciría los severos efectos adversos de los actuales tratamientos

►El receptor de esta nanopartícula está expresado en 20 tipos de cáncer en los que se relaciona con mal pronóstico, por lo que este fármaco podría abrir una nueva vía terapéutica para otros tumores

La leucemia mieloide aguda es una enfermedad muy heterogénea cuyo tratamiento habitual es muy agresivo y con efectos secundarios severos. En la búsqueda de un nuevo fármaco más eficaz, investigadores del CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) han demostrado la eficacia de nanopartícula de creación propia que bloquea la diseminación de las células leucémicas en modelos animales de leucemia mieloide aguda y que ataca directamente las células tumorales sin dañar las sanas, minimizando los efectos adversos.

Los resultados de esta investigación, con la participación de los grupos del CIBER-BBN en el Instituto de Investigación del Hospital de Sant Pau – IIB Sant Pau y el Instituto de Investigación contra la Leucemia Josep Carreras (Ramón Mangues, Isolda Casanova, Víctor Pallarès, Aïda Falgàs y Jorge Sierra), y de la Universidad Autónoma de Barcelona (Antonio Villaverde y Esther Vázquez), han sido publicados en la revista científica internacional Journal of Hematology and Oncology.

  • Grup Dr. Mangues

    Grupo de Investigación en Oncogénesis y Antitumorales liderado por el Dr. Mangues

Los investigadores han desarrollado un nanofármaco que está dirigido específicamente a las células leucémicas, formado por una nanopartícula unida a una toxina, llamada auristatina, que es entre 10 y 100 veces más potente que los fármacos utilizados habitualmente en clínica. Según explica el jefe de grupo del CIBER-BBN y del Grupo de Investigación en Oncogénesis y Antitumorales del Instituto de Investigación del Hospital de Sant Pau – IIB Sant Pau, Ramón Mangues, “hemos diseñado un nanoconjugado gracias a la ICTS Nanbiosis del CIBER-BBN que se dirige únicamente a las células que tienen en su superficie un receptor que está sobreexpresado en células leucémicas llamado CXCR4. De esta manera, la partícula entra y libera la auristatina en las células que tienen este receptor”.

El CXCR4 está sobreexpresado en un porcentaje elevado de células leucémicas de pacientes con mal pronóstico o aquellos que han recaído, lo que podría tener un gran impacto clínico sobre los pacientes de leucemia mieloide aguda. Asimismo, este receptor está sobreexpresado en más de 20 distintos tipos de cáncer en los que también se relaciona con mal pronóstico, por lo que podría ser evaluado en un futuro como posible tratamiento de otros tumores de alta prevalencia.

Bloquea la diseminación de las células leucémicas en ratones sin toxicidad

La nanopartícula diseñada es capaz de internalizar en las células leucémicas a través del receptor CXCR4 y eliminarlas. Además, también han demostrado su capacidad de bloquear la diseminación de las células leucémicas en un modelo animal de ratón sin producir ningún tipo de toxicidad ni efecto adverso. Por tanto, este fármaco dirigido a las células leucémicas podría ayudar a los pacientes de LMA que no pueden ser tratados con los fármacos actuales por su alta toxicidad, como aquellos de avanzada edad o con otras características no favorables al tratamiento convencional.

Ramón Mangues explica además que “también se podría tratar a aquellos pacientes que han desarrollado resistencia a los fármacos o a los que han sufrido una recaída tras ser curados, ya que sus células leucémicas tendrían una alta expresión del receptor CXCR4, diana del nanofármaco. Por tanto, existe un amplio espectro de pacientes que podrían beneficiarse de este nuevo tratamiento teniendo estos resultados una gran relevancia clínica si se confirma su efectividad en futuros ensayos clínicos”.

Dr. Manel Esteller is recognized as the most cited biomedical scientist located in Spain

►The researcher Manel Esteller, director of the Josep Carreras Leukaemia Research Institute, and leader in Cancer Epigenetics, is recognized as the most influential biomedical researcher located in Spain.

  • Dr. Manel Esteller

Manel Esteller, Director of the Josep Carreras Leukaemia Research Institute, ICREA Researcher and Professor of Genetics at the University of Barcelona is the biomedical scientist located in Spain whose discoveries are the most cited in Spain, according to the latest edition of the classification in Webometrics, prepared by the cyber metrics group of the Spanish National Research Council (CSIC).

The ranking is based on the more than 200 million academic documents registered in the Google Scholar database, where information from 82,000 Spanish researchers are collected. The ranking includes both Spanish researchers working abroad and those working in Spain. The ranking follows the so-called “h-index,” one of the most widely used indicators to evaluate the impact of a researcher’s contributions throughout his or her career. It was devised by physicist Jorge Hirsch to combine in a single piece of data the quantity and quality of a scientist’s research.

Dr. Manel Esteller’s research focuses on the epigenetic mechanisms involved in the emergence and progression of human diseases, mainly cancer. The results derived from his studies have allowed, in addition to knowing the molecular basis of various diseases, the development of innovative diagnostic tools and new treatments for them.

Identified the genetic landscape of Myelodysplastic/Myeloproliferative Neoplasms

►Researchers from the MDS Group of the Josep Carreras Leukaemia Research Institute and the Munich Leukemia Laboratory map the mutations that can ease and accelerate the diagnosis of Myelodysplastic/Myeloproliferative Neoplasms rare malignancies.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) is a group of rare malignancies with overlapping features from myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), that include a variety of diseases depending on their phenotype (haematological and morphological characteristics). Adult MSD/MPN include Chronic Myelomonocytic Leukaemia (CMML), atypical chronic myeloid leukaemia (aCML), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) and MDS/MPN unclassifiable (MDS/MPN-U).

Due to overlap features among these diseases, as well as with MDS and MPN, differential diagnosis remains a challenge. For hematologists, deciding a diagnosis of these rare malignancies is a broad process that involves the use of different tests and techniques, a long way of analyses, tests, prognosis evaluation and decision making. In the end, the lack of knowledge that could allow a more precise and fast diagnosis to decide the best treatment and enhance good prognosis prolongs the patient’s pain.

Laura Palomo and her colleagues from the MDS Group coordinated by Francesc Solé, from the Josep Carreras Leukaemia Research Institute, in a study led by Torsten Haferlach and his team from the Munich Leukemia Laboratory (MLL), have recently published a study in the Journal Blood that reveals the molecular landscape of these diseases and the combination of genes exclusively mutated in each of these rare neoplasms. These findings provide a useful tool to complement current diagnostic workup in MDS/MPN patients.

“In previous studies, over 90% of MDS/MPN harbored somatic mutations in a group of known genes, which are related to their pathophysiological features and play a role in their clinical heterogeneity, but none of them was specific of MDS/MPN. In our study, made with whole genome data from a cohort of 367 patients with MDS/MPN, we identified genotype-phenotype associations and potential diagnostic and prognostic molecular markers that could translate to medical practice. We also wanted to provide novel insights into the clonal hierarchy of mutations of MDS/MPN.” Says Laura Palomo.

Researchers found recurrent combinations of mutations exclusive to some extent to CMML, aCML, and MDS/MPN-RS-T, while MDS/MPN-U show heterogeneous features that overlap with the other MDS/MPN, but that can be classified according to their molecular profile. For Palomo, “It is imperative to include targeted DNA sequencing techniques in clinical hematology laboratories to improve the diagnosis and risk stratification of these hematological malignancies.”

This project is part of an international effort from the MLL, the 5000 Genomes Project. This project includes whole genome and transcriptome sequencing of 5000 patients with haematological neoplasms and is funded by the Torsten Haferlach Leukämie Diagnostikstiftung.

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    Myelodysplastic Syndromes Research Group from Josep Carreras Leukaemia Research Institute

Professor Andreas Neubauer, head of the Carreras Leukemia Center in Germany, cures a COVID-19 patient with an anticancer drug

►Head of the Carreras Leukemia Center at Marburg University Hospital and vice-president of the José Carreras Leukämie Stiftung, Professor Dr. Andreas Neubauer, plans scientific study on the use of an immune inhibitor against this viral disease.

Professor Dr. Andreas Neubauer and his team from the Marburg University Medical center is raising hope for a COVID-19 cure. He tested, with success, the cancer drug ruxolitinib for the first time to cure a patient suffering from acute respiratory distress syndrome (ARDS) after infection with the coronavirus SARS-CoV-2.

Prof. Neubauer and his colleagues report on the successfully treated case in the scientific journal Leukemia, in the article “Ruxolitinib for the treatment of SARS-CoV-2 induced acute respiratory distress syndrome (ARDS).”

The German Federal Institute for Drugs and Medical Devices has now approved a clinical trial where the researchers hope to investigate further the use of ruxolitinib for the treatment of COVID-19-associated ARDS.

Professor Dr. Andreas Neubauer teaches hematology and oncology at the University of Marburg. Since 2009, he has headed the Carreras Leukemia Center at Marburg University Hospital and is the Vicepresident of the Deutsche Jose Carreras Leukämie Stiftung.

“We knew from Chinese publications that a so-called cytokine storm characterizes patients with a severe and even fatal course of the disease,” Neubauer says. “During a cytokine storm, the body is flooded with substances that stimulate the immune system.” This overreaction of the body’s defense system damages the tissue — making it all the easier for the invading virus to spread.

Neubauer thought that the patient might respond to ruxolitinib, a drug initially used in cancer treatment. It inhibits enzymes in the body involved in excessive inflammatory reactions. “We suggested to our colleagues who were treating the patients with COVID-19 that the cancer drug might be able to prevent the life-threatening effects brought on by the inflammatory damage to lung tissue,” Neubauer says.

“We faced a difficult decision,” adds Professor Dr. Hinnerk Wulf, Director of the Department of Anesthesia and Intensive Care. “It was uncertain whether the theory would also work in practice; after all, the experimental treatment was also associated with risk.” The condition of the Marburg University Medicine patient did improve after she received ruxolitinib. The treatment team noted clinical stabilization as well as rapid improvement in respiration and heart function.

The success of the treatment was not an isolated case. The team in Marburg also administered the cancer drug to several other patients to control a severe course of the disease. “It turned out well in the end for all patients who received the cancer drug for longer than one week,” Neubauer explains. A team lead by Professor Dr. Paul Graf La Rosée at Schwarzwald-Baar Hospital has also reported the successful use of the immune inhibitor, although in less severe cases and the results are awaiting publication.

“The time between the onset of ruxolitinib administration and health improvement is so short that it is reasonable to assume that the drug contributed to the favorable clinical course,” Neubauer explains. 

The José Carreras Leukämie Stiftung has provided financial support for this research work, which has also been cited in the prestigious journal Nature.

  • Carreras Leukemia Center in Germany