While cure rates for childhood acute lymphoblastic leukemia (ALL) approach 90% in the current era, relapse remains the most common cause of treatment failure and death. Advances in cancer genetics have recently made several important discoveries, such as the identification of a particular group of patients who display a “genetic signature” similar to that of Philadelphia (Ph) chromosome positive ALL; hence, known as Ph-like ALL. It has also been shown that these patients respond to a special group of chemotherapy agents called “tyrosine kinase inhibitors” (TKIs) such as imatinib and dasatinib. We hope that combining TKIs with chemotherapy will cure most of these patients but we anticipate that some may still relapse as a result of developing resistance to these TKIs, similar to how certain infections can become resistant to antibiotics. Therefore, the objective of our study is to identify how this resistance happens and to further identify new medicines that can be used to treat patients with relapsed Ph-like ALL.