B-progenitor acute lymphoblastic leukemia (B-ALL) is the commonest childhood malignancy and remains a leading cause of death in children and young adults. Current therapeutic approaches involve intensive combination chemotherapy, which fail in up to one-quarter of patients. New treatment approaches directed against rational therapeutic targets are required. Recent genomic profiling of ALL has identified several genetic alterations associated with a high risk of treatment failure. Deletion or sequence mutation of the lymphoid transcription factor gene IKZF1 (IKAROS) is associated is associated with a high rate of leukemic relapse, and testing for IKZF1 alterations at diagnosis may aid risk stratification. A subset of B-ALL patients with IKZF1 alterations have a transcriptional profile similar to BCR-ABL1 positive ALL, and these patients commonly have novel rearrangements and mutations resulting in aberrant cytokine receptor signaling and activation of kinase signaling cascades, including rearrangement of CRLF2 and activating mutations of Janus kinases (JAK1 and JAK2). JAK inhibitor therapy is under investigation in children with relapsed and refractory malignancies, including leukemia.
- Received October 4, 2010.
- Revision received November 12, 2010.
- Accepted November 16, 2010.