The identification of mutations in the JAK2 gene involved in Down's syndrome-associated acute lymphoblastic leukaemia (ALL) could lead to new drugs to target this form of leukaemia. This is the conclusion of authors of an Article published early Online and in an upcoming Edition of The Lancet, written by Dr Shai Izraeli, Sheba Medical centre, Ramat Gan, Israel, and colleagues.
Leukaemia is a cancer of the blood or bone marrow and is characterized by abnormal proliferation (production by multiplication) of white blood cells (leukocytes); while Down's Syndrome is caused by the presence of an 'extra' chromosome 21 (humans normally have 23 pairs of chromosomes). Children with Down's syndrome usually have impairment of cognitive ability and physical growth; they also have a 20-fold increased risk of developing acute leukaemia, including ALL. The researchers tested the hypothesis that mutations in JAK2 might be a common molecular event in ALL associated with Down's Syndrome – because JAK2 mutations have been implicated in cancers affecting other types of white blood cell (myeloproliferative disorders).
An analysis of bone marrow samples from 87 patients with Down's syndrome-associated ALL revealed that 16 (18%) had somatically* acquired JAK2 mutations; and children with a JAK2 mutation were younger at diagnosis with ALL (4.5 years) compared those who did not have this mutation (8.6 years). Five mutations (alleles) were identified, each affecting a single amino-acid residue in the protein coded by the gene, known as R683.
The authors conclude that a specific association exists between the type of somatic mutation in the JAK2 gene and the development of conditions such as ALL. They say: "Somatically acquired R683 JAK2 mutations define a distinct acute lymphoblastic leukaemia subgroup that is uniquely associated with Down's Syndrome. JAK2 inhibitors could be useful for treatment of this leukaemia."
In an accompanying Comment, Dr Charles G Mullighan, St Jude Children's Research Hospital, Memphis, TN, USA, discusses how resequencing of entire genomes is now feasible and is underway in leukaemia and other tumours. He says: "These approaches, coupled with genome-wide analyses of alterations to DNA copy number and epigenetic* phenomena, will lay bare the genome of acute lymphoblastic leukaemia, and allow us to identify logical pathways for therapeutic intervention in this disease."
Dr Shai Izraeli, Sheba Medical centre, Ramat Gan, Israel T) +972-52-6666360 E) Shai.Izraeli@sheba.health.gov.il
Dr Charles G Mullighan, St Jude Children's Research Hospital, Memphis, TN, USA T) 1-901-595-3387 E) Charles.mullighan@stjude.org
Notes to editors:
*Somatic – mutations that arise spontaneously in an individual's cells during life; ie, they are not mutations inherited from parents.
** epigenetics refers to changes in gene expression caused by environmental factors, not by changes in the underlying DNA sequence. These changes may remain through cell divisions for the remainder of the cell's life. Sometimes the changes last for multiple generations. However, there is no change in the underlying DNA sequence of the organism
Full Article and Comment: http://press.thelancet.com/JAK2final.pdf
Journal
The Lancet