2018 May 30

A busy start to 2018 for the Stem Cells and developmental cancer Group

The first group to move into the Campus Clínic-UB has now been working hard for four years.  We caught up with the group leader, Pablo Menéndez to review some of their recent successes.

The first group to move into the Campus Clínic-UB has now been working hard for four years.  The Stem cells, Mesenchymal Cancer and Development Group has grown and consolidated and have had a busy start to 2018; they have signed contracts for five new sources of competitive funding and published four new articles in scientific journals.  We caught up with the group leader, Pablo Menéndez to review some of their recent successes.

The first task of any group leader is to secure continued funding to pay for staff and for science.  This job has got harder and even more stressful in recent years due to an increase in the number of groups competing for funding and a decrease in funds available in many cases. 

“We have had good news from various places in the first part of this year,” says Menéndez, “We have been named as a Consolidated Research Group by the Generalitat (SGR-330) and as a group working here in a CERCA centre that doesn’t only mean access to funding, but it is also an important recognition,” he adds. “Clara Bueno, Associate Investigator in the group, has also been awarded a Spanish FIS grant as well as a private grant from the FERO Foundation, a private body with its origins in Barcelona, which is also a source of great satisfaction.”

The largest grants for research projects are awarded by the European Research Council, but they are also the most competitive of all.   Menéndez explains that the group has received a Proof of Concept Grant, one of only 5 awarded to Spain out of a total of 50.  Only holders of ERC grants can apply, “It is a prestigious award,” Menéndez tells us.  “It is not aimed at research, but to fund bringing inventions to the market, which means helping ERC-funded scientists set up new companies, file patent applications and attract capital to make their research marketable.   This is vital for us to be able to take our discoveries out of the laboratory and bring them to patients and we are very excited about it.”

This is not the only European money the group has attracted, they have two new post-doctoral investigators who are funded by ERC Marie Skłodowska-Curie actions aimed at helping young researchers move to a different laboratory and covering all their costs.   Samanta Zanetti and Talia Velasco are already hard at work in the group and we look forward to hearing more about them soon.

Apart from news of new sources of funding the group has published five new papers.  Menéndez explains how these reflects the different lines of attack to find the mechanisms behind the various forms of leukaemia they study.

A paper published in the prestigious journal Leukemia in March is the result of work by Cristina Prieto, a former PhD student in the laboratory in collaboration with several other European groups.   This work continues the work on the devastating disease in new-borns called infant pro-B acute lymphoblastic leukemia (B-ALL) and identifies a possible target for new therapies.

In another paper in Oncotarget, Prieto and the group publish more results on infant pro-B acute lymphoblastic leukemia (B-ALL).  Studying the disease in babies is not feasible as it is so rare and the patients tend to have very short lives.  In this work, Menendez’s team continue to perfect a model in which they can study a particular strain of mouse that develops the same disease.

A third paper published on-line in Epigenomics in April is also a collaboration and describes a chemical change in the DNA of developing T cells of the human immune system.  This change, called methylation, is part of the mechanism that controls the normal functioning of cells, but it is also implicated in some cancerous processes. 

The fourth scientific contribution has been in a collaboration with Prof Marisa Toribio who leads the T-ALL group at the Severo Ochoa Molecular Biology Institute in Madrid. In this study, just published in the top-tier Journal of Clinical Investigation, Toribio`s group unravelled a new molecular mechanism involving Notch pathway and the molecule CD44 which is key for the initiation and evolution of T-ALL.

Finally, in a paper accepted for publication soon in OncoImmunology the group have collaborated on a complex study of the interaction of treatment resistant acute myeloid leukemia (AML) cells and the bone marrow.  They studied the use of the new generation immunomodulatory drugs (IMiDs), affective for some other forms of leukemia, to see if they could combat resistance to therapy in AML.

We commented to Menéndez that all this activity reflects much of the life in a large busy group and the relentless cycle of looking for funding and publishing results.  Projects are continually starting and finishing and there is a constant pressure to find funds to pay for the next round.  Here we have seen students completing their work; new scientists arriving; collaborations with Spanish and international groups looking at several different aspects of the leukemia process in different lines of research and planning to bring discoveries to the market. “And that is not counting all the other things we have to do,” he laughs, “Most of the time we scientists feel like the Red Queen in Alice in Wonderland who said, ‘"it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!"

References

NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL

C Prieto, B López-Millán, H Roca-Ho, R W Stam, D Romero-Moya, F J Rodríguez-Baena, A Sanjuan-Pla, V Ayllón, M Ramírez, M Bardini, P De Lorenzo, M G Valsecchi, M Stanulla,8M Iglesias, P Ballerini, Á M Carcaboso, J Mora, F Locatelli, A Bertaina, L Padilla, J Carlos Rodríguez-Manzaneque, C Bueno,* and P Menéndez,*

Leukemia. 2018; 32(3): 633–644. Published online 2017 Oct 17. Prepublished online 2017 Sep 25. doi:  10.1038/leu.2017.294   PMCID: PMC5843903  PMID: 28943635

Epigenome-wide analysis reveals specific DNA hypermethylation of T cells during human hematopoietic differentiation

J Ramón Tejedor‡, Clara Bueno‡, Isabel Cobo, Gustavo F Bayón, Cristina Prieto, Cristina Mangas, Raúl F Pérez, Pablo Santamarina, Rocío G Urdinguio, Pablo Menéndez, Mario F Fraga & Agustín F Fernández
EPIGENOMICS, Published Online:5 Apr 

The NOTCH1/CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model

Marina García-Peydró, Patricia Fuentes, Marta Mosquera, María J. García-León, Juan Alcain, Antonio Rodríguez, Purificación García de Miguel, Pablo Menéndez, Kees Weijer, Hergen Spits, David T. Scadden, Carlos Cuesta-Mateos, Cecilia Muñoz-Calleja, Francisco Sánchez-Madrid, and María L. Toribio
J Clin Invest. 10.1172/JCI92981.

The AF4-MLL fusion transiently augments multilineage hematopoietic engraftment but is not sufficient to initiate leukemia in cord blood CD34+ cells.

Prieto C, Marschalek R, Kühn A, Bursen A, Bueno C, Menéndez P.
Oncotarget. 2017 Oct 10; 8(47): 81936–81941.
Published online 2017 Jul 26. doi:  10.18632/oncotarget.19567

IMiDs mobilize Acute Myeloid Leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML
OncoImmunology (in press)

Funding

This group is supported by and has received funding from the European Research Council (ERC) (CoG-2014-646903; Spanish Ministry of Economy and Competiveness (SAF2016-4603 and RTC2016-4603-1), the Generalitat of Catalunya (SGR 330), the Institut Carlos III (ISCIII/FEDER PI14-01191) and the Associación Española Contra el Cáncer (AECC-CI2015).

Pablo Menendez is an ICREA Research Professor at the IJC.