Identification of mutant alleles of JAK3 in pediatric patients with acute lymphoblastic leukemia

Abstract

Children with acute lymphoblastic leukemia (ALL) have an 80% chance of long-term survival. Despite the high rate of cure, children relapse, and recurrent ALL is difficult to cure with chemotherapeutic regimens. Therefore, improved biological understanding of ALL and the development of rationally designed therapeutics targeting molecules associated with the pathogenesis of ALL are essential. We identified missense and synonymous JAK3 mutations in 16 of 91 pediatric patients with ALL. The expression of JAK3^V722I mutant caused the cytokine-independent activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling and conferred the factor-independent growth of murine interleukin-3 (IL-3)-dependent pro-B Ba/F3 cells. Importantly, inhibition of JAK3 by the known JAK3 inhibitor CP-690 550 converted the Ba/F3-JAK3^V722I cells back to factor-dependent growth. These observations suggest that JAK3 may contribute to the pathogenesis of pediatric ALL and serve as an important therapeutic target which can be leveraged to improve outcomes for pediatric patients with ALL.

Keywords::

• Acute lymphoblastic leukemia
• mutant allele
• JAK3

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

This work was supported by the Children's Cancer Fund (Millwood, NY).

Supplementary material available online

Supplementary Table showing details of 91 clinical samples.