Chev Pat Pedulla CGSJ

Breaking News

MEDIA RELEASE: September 2013

Australian researchers help uncover genetic causes of childhood leukemia

 

 

 

 

 

 

 

Current Projects

Leukemia Research

Professoe David Ziegler and Grand Prioe Pat PedullaThe Australian Grand Priory has pledged to fund Professor David Zeigler's research for a period of five years. This research into Protocol utilising next generation sequencing to identify the genetic cause of childhood Acute Lymphoblastic Leukaemia, is led by Professor Zeigler at the Sydney Childrens' Hospital in Randwick. The primary aim of this project is to identify the underlying genetic mutation that has led to the development of childhood acute lymphoblastic leukaemia (ALL) in a unique case of inherited ALL. The secondary aim is to test whether the mutated gene identified can be found in any of a large cohort of 800 cases of sporadically acquired childhood ALL. Our overall aim is to identify the genetic cause of childhood leukaemia, in order to ultimately facilitate the development of better treatments for leukaemia.

Background

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer, and despite improvements in treatment outcomes, the majority of children with relapsed ALL will ultimately die of their disease. In order to develop novel treatments, it is critical that we better understand the factors that lead to its development.

It is currently hypothesized that childhood ALL develops after multiple 'hits'.1 According to this 'multiple hits' hypothesis, haematopoietic stem cells are affected by a series of genetic and environmental hits that ultimately result in their transformation to acute leukaemic blasts.1 The genetic factors that are critical to this process remain almost completely unknown. Next generation sequencing (NGS) is a novel state of the art technique for sequencing an entire genome. However, the power of this technique is also a significant limitation. Sequencing the genome of cancer cells has revealed 2,500 different mutations, making it impossible to accurately determine the significance of each individual genetic change.2 Similarly, NGS performed on leukaemia samples has identified hundreds of different genetic mutations making it difficult to prove which are the critical leukaemogenic changes.3 A similar study performed exclusively on childhood ALL samples identified a common polymorphism that may contribute to childhood ALL, but no definitive genetic event was found.4 An alternative approach to screening leukaemic blast cells is to study the genotypic changes in rare persons who have an inherited predisposition to ALL. This approach has recently been employed in another childhood cancer – neuroblastoma – leading to the discovery that the ALK gene is mutated not just in familial cases, but also in many sporadic cases of the disease, and that it is a critical carcinogenic factor.5 This same methodology would provide a powerful tool for studying the genetic causes of ALL, however, is limited by the fact that in ALL cases of direct genetic inheritance are very rare.6 To date, no specific genetic mutation has been identified that leads to a familial case of childhood ALL.

We have now identified a remarkable family in which multiple family members have been affected by ALL in childhood or early adult life. The distribution of cases is highly suggestive of an autosomal dominant inheritance.

Impact and significance:

Together these factors provide a unique opportunity to understand the genetic cause of ALL and offers the chance to identify a genetic mutation that directly leads to childhood ALL. This may lead to the development of a genetic test that can identify a risk of developing ALL. Ultimately this may also facilitate the development of novel targeted therapies that may prevent or enhance the treatment of this potentially devastating disease.

 

Copyright © 2015 Sovereign Hospitaller Order of St John of Jerusalem