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U.S. National Institutes of Health
Cancer Diagnosis Program Cancer Imaging Program Cancer Therapy Evaluation Program Developmental Therapeutics Program Radiation Research Program Translational Research Program Biometric Research Branch Office of Cancer Complementary and Alternative Medicine
Last Updated: 04/25/2012


Childhood Cancer TARGET Initiative Acute Lymphoblastic Leukemia Discoveries

Children’s Oncology Group (COG) researchers collaborated with researchers from St. Jude Children’s Research Hospital, the University of New Mexico, and NCI as part of the Childhood Cancer TARGET Initiative to discover that the Ikaros gene (IKZF1) is altered in approximately 25 percent of children with high-risk acute lymphoblastic leukemia (ALL) ( 011309/page5) and is a highly significant independent predictor of poor outcome[1]. The gene expression signature of IKZF1-mutated BCR-ABL1 negative ALL is closely related to that of BCR-ABL1 positive ALL. The discovery of a new biologically-defined subset of ALL with very poor outcome with current treatment approaches has important prognostic and therapeutic implications.

The Childhood Cancer TARGET Initiative research team also discovered that activating mutations in the Janus kinase family (JAK1, JAK2, and JAK3) ( 2009/050509/page9#c) occur in approximately 10 percent of high-risk pediatric B-precursor ALL cases[2]. The presence of JAK mutations was significantly associated with alteration of IKZF1, and mutations were highly predictive for relapse. The transforming activity of the JAK mutations was blocked by JAK inhibitors, providing strong rationale to pursue inhibition of JAK signaling as a novel therapeutic intervention for JAK-mutated ALL. The COG Phase 1 Consortium is developing a clinical trial of a JAK inhibitor as an initial step in translating the TARGET Initiative discovery from the bench to the bedside.

  1. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009;360:470-480.

  2. Mullighan CG, Zhang J, Harvey RC, et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 2009:106;9414-8.