Acute lymphoblastic leukemia (ALL) is the most frequent childhood cancer. Whereas∼ 90% of pediatric ALL patients can be cured with current therapies, the prognosis for adult patients and children with relapsed disease is poor (Hunger an d Mullighan, 2015). Over the last decade, our understanding of the genetic basis of B lineage ALL (B-ALL) pathogenesis and treatment response has been revolutionized by high-resolution genomic and transcriptional profiling of large patient cohorts (Roberts and Mullighan, 2015). These studies reveal that a majority of patients with B-ALL harbor somatic mutations or focal deletions that disable genes encoding lymphoid transcription factors, including EBF1, PAX5, and IKZF1 (Kuiper et al., 2007; Mullighan et al., 2007; Roberts and Mullighan, 2015).

Approximately 5% of pediatric B-ALL patients have disease harboring the t (9; 22) translocation, forming what is commonly termed the Philadelphia (Ph) chromosome and resulting in expression of the oncogenic BCR-ABL1 fusion kinase. A novel disease subtype was recently defined based on a gene expression profile similar to Ph+ disease, termed Ph-like or BCR-ABL1-like B-ALL (Den Boer et al., 2009; Mullighan et al., 2009). The Ph+ and Ph-like disease subtypes have relatively high relapse rates and poor prognosis, and together comprise∼ 15% of pediatric and∼ 50% of adult B-ALL cases (Roberts et al., 2012, 2014; van der Veer et al., 2013). Somatic genetic alterations in IKZF1, which encodes the zinc finger transcription factor IKA ROS, occur in 50–70% of Ph+ and Ph-like B-ALL cases (Mullighan et al., 2008a, 2009; Den Boer et al., 2009; Roberts et al., 2012, 2014; van der Veer et al., 2013, 2014;