Understanding the genetic mechanisms of leukaemia development in children with Down syndrome

01 December 2011

Professor Irene Roberts, University of Oxford

Children with Down syndrome have a greatly increased risk of developing leukaemia. Professor Roberts is deciphering the genetic mechanisms underlying this increased risk in the hope of identifying new targets for the prevention and treatment of leukaemia in all children.

Amount of grant: £205,373  |  Date of award: December 2011

Professor Irene Roberts & Dr Paresh Vyas, University of Oxford; Professor Anastasios Karadimitris, Imperial College London.

Overview

Children with Down syndrome (DS) have a greatly increased risk of developing leukaemia. All babies and children with DS have well-defined abnormalities affecting production of blood cells, but leukaemia develops in only a minority of these children.

With this project, taking advantage of the unparalleled power of new technologies, the team seeks to identify the genetic mechanisms responsible for causing leukaemia in children with DS.

This work is likely to lead to the identification of new targets for the prevention and treatment of leukaemia in children both with and without DS.

Background

All babies and children with Down syndrome (DS) have abnormalities in the production of their blood cells.
Hollie has Down’s syndrome. In July 2009, she was diagnosed with leukaemia at just 14 months oldAlthough leukaemia develops in only a minority of these children, the risk of a child with DS developing leukaemia is much higher than for their non-DS peers. Children with DS have a 150-fold increased risk of developing acute myeloid leukaemia (AML) and a 33-fold increased risk of developing acute lymphoblastic leukaemia (ALL).

The mechanisms underlying this increased risk aren’t entirely clear but involve chromosome 21, a third copy of which is the underlying cause of Down syndrome, also known as Trisomy 21 (T21).

The leukaemic cells of many children without DS have additional copies of all or part of chromosome 21.

Leukaemia in Down syndrome provides a unique model to study the distinct steps in development of childhood leukaemia:

  • The research team has shown that T21 per se leads to abnormal blood cell production in all newborns with DS.
  • Around 8 per cent of newborns with DS present with Transient Myeloproliferative Disorder (TMD).
  • TMD spontaneously resolves in around 70 per cent of cases and progresses to acute leukaemia in the remaining 30 per cent of cases.

Understanding the genetic mechanisms

This project is likely not only to unfold the mysteries of leukaemogenesis in Down syndrome but also to illuminate the developmental mechanisms of childhood leukaemia in general.This work is being led by three world-leading authorities in the field of leukaemia and Down syndrome – Professor Irene Roberts and and Dr Paresh Vyas at the University of Oxford and Professor Anastasios Karadimitris from Imperial College London.

The team has access to a network of collaborating neonatal units and paediatric haematology units. From this network they will obtain samples of normal cord blood, DS cord blood, blood from babies and children with TMD, and blood from babies and children with AML and ALL.

Taking advantage of the latest genetic sequencing technology, the team will look for key differences in the genetic profiles of these samples.

This complex work should provide vital information about the processes underlying the development of leukaemia both in children with and without DS.

What difference will this project make?

This work should contribute significantly to knowledge about the development of childhood leukaemia and the mechanisms underlying this development – in children both with and without Down syndrome.

It is likely to lead to identification of new approaches for prevention and treatment of leukaemia in DS and childhood leukaemia in general.

Read more: Read Hollie's story | Acute lymphoblastic leukaemia (ALL)
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