Identifying Drug Resistant Mutations in Ph-like Acute Lymphoblastic Leukemia

Background
While cure rates for childhood acute lymphoblastic leukemia (ALL) approach 85% in the current era, relapse remains the most common cause of treatment failure and death. Teenagers and young adults with ALL have a worse outcome compared to younger children. The ALL Committee of the Children's Oncology Group has been focusing on finding new cures for patients who are at the highest risk of their leukemia coming back. 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. Ph-like ALL comprises approximately 15% of childhood ALL and more than 25% among young adults with ALL. Importantly, this group has poor survival rates compared to those without the "Ph-like" signature. 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.

Project Goal
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.