Researchers are closer to developing drugs to treat acute lymphoblastic leukemia (ALL) after identifying mutations in the JAK2 gene involved in Down’s syndrome, which is associated with this form of leukemia. Dr Shai Izraeli (Sheba Medical Centre, Ramat Gan, Israel) and colleagues explain their research in an article published early online and in an upcoming edition of The Lancet.

A cancer of the blood or bone marrow, leukemia is a disease characterized by abnormal reproduction of leukocytes, or white blood cells. Down’s syndrome is a genetic disorder that occurs when a human has a third copy of chromosome 21 rather than the normal 23 pairs of chromosomes. Not only does Down’s syndrome leave children with impaired cognitive ability and physical growth, but the condition also results in a 20-times increased risk of developing acute leukemia, including ALL. Since mutations of the gene JAK2 have been linked to cancers that affect other types of white blood cell (myeloproliferative) disorders, Dr Izraeli and colleagues hypothesized that mutations of JAK2 are a common molecular event found in Down’s syndrome-related ALL.

The tests required bone marrow samples from patients with Down’s syndrome-related ALL. Of 87 patients who met the necessary criteria, 18% (16) had somatically (spontaneous, not inherited) acquired JAK2 mutations. In addition, the researchers found that children with a JAK2 mutation were 4.1 years younger at ALL diagnosis than those children who did not have the mutation – 4.5 years vs. 8.6 years. The study revealed five mutations (alleles) that each affected a single amino-acid residue in the protein that the gene encoded, called R683.

Dr Izraeli and colleagues conclude that there is a specific association between the development of conditions such as ALL and somatic mutation in the JAK2 gene. They write: “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.”

Dr Charles G Mullighan (St Jude Children’s Research Hospital, Memphis, TN, USA) writes in an accompanying editorial about the substantial progress that has been made in resequencing entire genomes leukemia and other tumors. Mullighan writes: “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.”

Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down’s syndrome
Dani Bercovich, Ithamar Ganmore, Linda M Scott, Gilad Wainreb, Yehudit Birger, Arava Elimelech, Chen Shochat, Giovanni Cazzaniga, Andrea Biondi, Giuseppe Basso, Gunnar Cario, Martin Schrappe, Martin Stanulla, Sabine Strehl, Oskar A Haas, Georg Mann, Vera Binder, Arndt Borkhardt, Helena Kempski, Jan Trka, Bella Bielorei, Smadar Avigad, Batia Stark, Owen Smith, Nicole Dastugue, Jean-Pierre Bourquin, Nir Ben Tal, Anthony R Green, Shai Izraeli
The Lancet (2008).
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Written by: Peter M Crosta