The role of MYBL2 in the age-related development of blood disorders

Lead Research Organisation: University of Birmingham
Department Name: Immunity and Infection

Abstract

Our ability to maintain a supply of healthy functional blood cells throughout our lives is absolutely dependent on the presence in our bone marrow of specialized stem cells. Like other stem cells in the body, these blood stem cells serve to provide a supply of mature cells as required and at the same time are able to make copies of themselves so that they do not become depleted throughout life. As we age, the blood stem cells can gradually acquire mutations in their genetic material sometimes leading to the appearance either of blood disorders in which either the normal number of type of blood cells produced is disrupted or a leukaemia arises. A protein that we know to be critical to limit genetic damage as cells divide is known as MYBL2, and loss of the gene coding for this appears to be linked to certain age-related blood disorders and leukaemia. I have generated a mouse model mimicking the way in which MYBL2 is altered in some patients with blood disorders and I wish to use this to study the precise way in which changes in this protein in stem cells can cause blood diseases as we get older. The outcomes of the project should provide new information to aid diagnosis and prognosis, and may lead to novel treatments for leukaemia and age-related decline in stem cell function.

Technical Summary

The haemopoietic system is prone to age-related disorders ranging from deficits in functional blood cells to the development of a variety of neoplastic states. Haemopoietic neoplasms often involve defining cytogenetic abnormalities, frequent amongst which is a deletion in the long arm of chromosome 20 (del20q). MYBL2, a key protein involved in the maintenance of genome integrity, is encoded within the minimum del20q region, suggesting a causative role for the factor in disease onset or progression.

I have demonstrated that mice expressing half the normal level of MYBL2 are susceptible to the development of myeloid disorders with age. Moreover, analysis of global expression studies conducted with cells from patients with myelodysplastic syndrome (MDS) confirmed that down regulation of MYBL2 expression levels correlates with poor prognosis (in refractory anaemia with excess blasts (RAEB)), regardless of the cytogenetic abnormality. The importance of MYBL2 in myeloid neoplasms is supported by a strong correlation between MYBL2 RNA levels and expression of a subset of genes related to cell cycle checkpoint control in cells from patients with MDS.

This project will utilize the mouse model of MYBL2 haploinsufficiency as a tool to study the molecular mechanisms of initiation and progression of haematological malignancies during ageing. The project will also investigate the molecular mechanisms leading to down-regulation of MYBL2 observed in MDS patients that do not exhibit del20q.

If it can be validated that down-regulation of MYBL2 is related to MDS with bad prognosis, then MYBL2 could potentially serve as prognostic biomarker of disease progression and have an impact in prospective therapeutic strategies for MDS patients.

Planned Impact

Impact on Knowledge - New information on the the molecular mechanisms that govern blood disorders during ageing will be generated by this project. This will be disseminated through publication in international journals and as well through channels such as the annual Molecular Haematology meeting (held in London), stem cell centre, BUSCC, and the regional stem cell network, MSCA.

Impact on Communication and Engagement - This will be achieved through the auspices of BUSCC and as part of the University of Birmingham Heroes campaign. Events will be held locally in the University or the city of Birmingham at which the public can engage in informed debate about a variety of issues related to stem cell science.

Impact on health and quality of life - The research in this project will not be only fundamental research, but will also study blood disorders using human samples. There will be opportunities to communicate the output to the local clinical haematology community as a part of this type of collaborative projects that are more translational. Long-term, the findings from this project should impact on health issues ranging from prognosis, the treatment of MDS and alleviation of age-related declines in stem cell function.

Impact on International Collaboration - This project will help to mantain an already established international collaboration with the group of Robert Kralovics in Vienna.

Impact on People - The project will lead to training of a postdoctoral staff, and will impact on the training of others in the laboratory, including PhD students, undergraduate students and master students. The expertise of the principal applicant and collaborators, and the new knowledge gained will be of use to several other research groups in the local research environment, as well as the wider community in Birmingham.

Impact on the Economy - We will continue to contribute to development of the local science infrastructure and in providing skilled researchers needed for academia and industry, and this is of particular relevance given the Science City status held by Birmingham and what this means in terms of linking academic output to local industries.
 
Description MRC proximity to Discovery
Amount £11,000 (GBP)
Organisation University of Birmingham 
Sector Academic/University
Country United Kingdom
Start 03/2017 
End 09/2017
 
Description Preliminary data Award
Amount £4,937 (GBP)
Organisation University of Birmingham 
Sector Academic/University
Country United Kingdom
Start 02/2016 
End 05/2016
 
Description Program grant LLR
Amount £1,400,000 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 12/2017
 
Description Saudi Government studentship
Amount £80,000 (GBP)
Organisation Government of Saudi Arabia 
Sector Public
Country Saudi Arabia
Start 04/2017 
End 04/2021
 
Title immunofluorescences 
Description Setting up fixation conditions to use double immunfluorescence staining for the same sample to reduce number of animals per experiment to half. 
Type Of Material Biological samples 
Provided To Others? No  
Impact Reduce number of animals to half by being able to study two proteins at the same time in the same biological sample 
 
Description Assocaition between MYBL2 haploinsufficiency and Jak2V617F mutation in blood disorders 
Organisation State University of New York
Country United States 
Sector Academic/University 
PI Contribution MTA agreement with university of New York for them to cross our MYBL2 mice with their Jak2 mouse model
Collaborator Contribution No contributions yet
Impact No outputs yet
Start Year 2017
 
Description MYBL2 in AML 
Organisation Hospital La Fe
Country Spain 
Sector Hospitals 
PI Contribution Intellectual Input, hosting PhD students
Collaborator Contribution Intellectual input, access to data http://dx.doi.org/10.1016/j.leukres.2013.09.015
Impact http://dx.doi.org/10.1016/j.leukres.2013.09.015
Start Year 2009
 
Description MYBL2 in MDS 
Organisation Austrian Academy of Sciences
Department Research Centre for Molecular Medicine
Country Austria 
Sector Academic/University 
PI Contribution Genetically modified mice: B-Myb conditional KO mouse
Collaborator Contribution Acces to data and equipment as well as intellectual input
Impact PMID22910183
Start Year 2010
 
Description MYBL2 in MDS using B-myb mouse model 
Organisation University Duisburg-Essen
Country Germany 
Sector Academic/University 
PI Contribution An MTA agreement has been established so the group of Dr Stefan Heinrichs can use our Bmyb mouse models to study cooperative mutations in the development of MDS. (sharing material)
Collaborator Contribution Sharing experiment and knowledge
Impact Collaboration just started (November 2015, MTA agreement completed in January 2016).
Start Year 2015
 
Description genome stability DNA damage studies 
Organisation University of Birmingham
Department School of Cancer Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Intelectual input and access to equipment and material
Collaborator Contribution Intellectual input and access to equipment and material
Impact PMID22945645
Start Year 2011
 
Description Astra Zeneca 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Talk to Astra Zeneca about our reserach to look for common points and possible collaboratio
Year(s) Of Engagement Activity 2016
 
Description Birmingham cancer showcase 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The labs were opened for people to come and visit and ask questions about our research in cancer and blood disorders.
We organized ourselves in different teams to explain them our research, the importnce, what we wanted to achieve and let them do "experiments" such as DNA extraction from strwberries or looking blood samples through the microscope etc.

Members of the public and patients with blood disorders were pleased with what they saw, made questions and enjoyed their visits.
Year(s) Of Engagement Activity 2015
URL http://www.birmingham.ac.uk/university/colleges/mds/events/2015/06/BirminghamCancerShowcase.aspx
 
Description Bloodwise Grant Holder day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Grant Holder day for Bloodwise in which there were not only presentations but as well the possibility to talk to director of the funding body who gave an explanation of the bankruptcy suffered by the charity and the plans for the future.
Year(s) Of Engagement Activity 2016
 
Description Copenaghen Congress Stem Cell Niche 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Congress in Copenhagen organized by DanStem.
I presented a poster related to our work on HSC and Double strand break it gave me the possibility of discussing my work with renown scientists such as Eirini Pappapetrou, Vonny Eaves and Domique Bonnet.
the meeting was really well organized with many events aim to mix people and to maximize interaction.
I was also chosen to be one of the judges for best postdoctoral researcher poster .
Year(s) Of Engagement Activity 2018
URL https://danstem.ku.dk/news/the-stem-cell-niche-conference-2018/
 
Description Genome Stability Network meeting, Cambridge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Genome stability network meeting, held in Cambridge.
The audience engaged with were team leaders, postdoctoral reearchers and PhD students working in the field.
We also counted with memebers of Industry such as Astra Zeneca and Nobel Prize 2015 Tomas Lindhal.
Year(s) Of Engagement Activity 2016
URL http://genomestabilitynetwork.org.uk/UK_GSN/Meetings_files/GSN_prog_2016.pdf
 
Description Laila Shadowing 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 3 pupils fro primary school visiting for career decision

students understood what career in research would be.
Year(s) Of Engagement Activity 2014
 
Description Molecular hameatology meeting Lonon 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Moleculal hematology meeting to interact and network with other groups within the field. Aside of the talks, the coffee breaks and lunch were really important for engaging with other groups and discus about our work.
Year(s) Of Engagement Activity 2016
 
Description Open day Cancer Research 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact General aundience interested on teh Research conducted at teh University of Birmingham, specifically related to leukaemias. some of them were patients that have pre-leukaemiac conditions and were treated on the QE hospital.
Year(s) Of Engagement Activity 2016
 
Description Open day at University 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Open day to showcase our research. The audience was quite interested on what was the cost of the different equipment and were amazed by the cost of research.
Year(s) Of Engagement Activity 2017
 
Description Orgnaization of a national meeting (MERCIA Stem Cell Alliance) December 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I organized a workshop for Undergraduate students within the MERCIA Stem Cell Alliance community. 70 undergarduate students participated in this workshop held t University of Birmingham.
The second day of the meeting was hels at theStudi (Birmingham), with 200 delegates.

the diea is to bring together basic scientis, NHS, and industry together within the stem cell field.

The meeting was really a success, industry is already asking when the next meeting will be held wishing to sponsor it. This meeting gave me and the University greater visibility.
Year(s) Of Engagement Activity 2018
URL https://www.birmingham.ac.uk/university/colleges/mds/events/2018/12/Eighth-Annual-Scientific-Meeting...
 
Description Paloma Shadowing 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Shadowing a 17 year old student and 2 undergraduate students from Brazil during summer.

Lots of discussion, questions and interest.



They just really loved to be in a lab, in fact the 7 years old did not want to come back to school, wanted to start unievrsity and become a sceintist straight away.

The 2 undergraduates students have decided to follow a career in Science and are finishing their degrees in order to do so.
Year(s) Of Engagement Activity 2015
 
Description Poster IPSc and reprogramming in Copenhagen conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Congress in Copenhagen organized by DanStem.
I presented a poster related to our work on reprogramming, but the congress of around 150 scientists was broader than reprogramming, and had the opportunity to discuss my work related to iPSC as well as haematopoietic stem cells and genomics with renown scientists such as Richard Young, Emmanuelle Passague, Valentina Greco, Veronique Azuara etc.
the meeting was really well organized with many events aim to mix people and to maximize interaction.
I was also chosen to be one of the judges for best postdoctoral researcher poster .
It alos gave me the opportunity to meet with my collaborator Keisuke Kaji.
Year(s) Of Engagement Activity 2016
URL http://danstem.ku.dk/the-stem-cell-niche-2016/
 
Description Shadowing undergraduate studnets 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact 2 undergraduate medical students attended my lab during one week, they saw how research is conducted and questioned about our research , as a consequence of this one of the students is planning to intercalate next year.
Year(s) Of Engagement Activity 2016
 
Description patients with MDS/AMl visiting the lab 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact 3 patients suffering with blood disorders visited the lab and were explained our research and showed the different equipment we had in the lab to carry on the research. They seemed quite interested and impressed with the type of research we were doing.
Year(s) Of Engagement Activity 2016