Investigating the onset of leukaemia in children with Noonan syndrome

03 July 2015
Professor Anthony Whetton, University of Manchester

Children with the genetic disorder Noonan syndrome (NS) have a high risk of developing leukaemia. Professor Whetton is examining differences in the blood stem cells of NS patients who did and did not develop leukaemia to increase our understanding of what causes a blood stem cell to become leukaemic and find targets for treatment. Not only will this offer the opportunity to develop new treatments, but it will contribute significantly to knowledge about the mechanisms underlying leukaemia development.

Amount of grant: £234,527 | Date of award: June 2014

Overview

Juvenile myelomonocytic leukaemia (JMML) is a chronic (slowly developing) form of leukaemia occurring in children, most commonly those under four years of age. It is a difficult disease to treat. The only curative therapy is stem cell (bone marrow) transplantation, but this is not suitable for all children. Chemotherapy can be used to control the disease but does not offer a cure.

Development of JMML is linked with a number of genetic disorders, including Noonan syndrome (NS), which carries a one in 10 risk of developing JMML.

The biological mechanism governing why some children with NS develop JMML while others do not is still unclear.

A gene called PTPN11 is found to be mutated in around half of cases of NS; PTPN11 is also commonly mutated in the blood stem cells of non-NS JMML patients.

In this project, Professor Whetton and colleagues are examining differences in the blood stem cells of NS patients who did and did not develop JMML to increase our understanding of what causes a blood stem cell to become leukaemic.

They will use state-of-the-art technology called proteomics to compare NS/JMML blood stem cells to NS/non-JMML blood stem cells. They will compare all the proteins within the NS/JMML cells to those within the NS/non-JMML cells and identify changes in quantities of and/or modifications to specific proteins.

They will couple their protein data with genetic data from their colleagues at Mount Sinai School of Medicine who made the stem cell lines that will be used in this project, creating an overview of the leukaemia-specific differences between the NS/JMML and NS/non-JMML cell lines.

Not only will this offer the opportunity to develop targeted treatments for JMML, but it will contribute significantly to knowledge about the mechanisms underlying leukaemia development.

About the research team

The work will be carried out in the state-of-the-art Stem Cell and Leukaemia Proteomics Laboratory (SCALPL) at the University of Manchester, led by Professor Anthony Whetton.

The SCALPL team are focused on the development of primitive blood stem cells and how this development is affected by leukaemia-causing oncogenes. Their expertise in stem cell and leukaemia biology is uniquely combined with expertise in the field of proteomics (the study of proteins).

Professor Whetton will work in close collaboration with colleagues based at Mount Sinai School of Medicine in New York: Professor Bruce Gelb and Professor Ihor Lemischka.

Professor Gelb is an internationally-renowned geneticist and paediatric cardiologist; he is internationally renowned for his research into the genetic causes of NS, particularly mutations in PTPN11, and has published extensively in the field.

Professor Lemischka is a world-leading stem cell biologist who, in collaboration with Professor Gelb, created the NS/JMML and NS/non-JMML stem cell lines to be used in this project. Professor Lemischka has recently joined the University of Manchester on a 20 per cent basis where he will share his wealth of experience in differentiation of primitive stem cells into blood cells with the Manchester-based team.

What difference will this project make?

This work will contribute significantly to knowledge about the development of childhood leukaemia and the mechanisms underlying its development – in children both with and without Noonan syndrome.

Any differences identified will allow a better understanding of the biology of the disease, offering the potential to develop much-needed new treatments.  

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