The mission of the laboratory is to study primary patient leukemia samples in order to identify novel genetic alterations and incorporate them into algorithms for diagnosis, minimal residual disease monitoring, and for the identification of novel therapeutic approaches.
My career as a pediatric hematologist-oncologist has focused on conducting translational studies in childhood leukemia, specifically Acute Lymphoblastic Leukemia (ALL) and Juvenile Myelomonocytic Leukemia (JMML). I have been heavily involved with initiatives in the Children’s Oncology Group (COG) to improve risk stratification for childhood ALL. Within the COG, I am Vice Chair of Biology of the ALL Committee and was one of the Study Co-Chairs of AALL03B1, the Classification of Acute Lymphoblastic Leukemia. AALL03B1 was the largest risk stratification trial in the history of childhood leukemia research, having enrolled over 11,200 children. AALL03B1 incorporated clinical features, genetics of leukemia blasts, and measures of early response in order to identify the most appropriate therapies for subgroups of patients. Recently, we have identified a novel subgroup of patients with a number of kinase fusions or genetic alterations that will activate kinase signaling. FDA approved, shovel-ready drugs, such as dasatinib are available for such patients and the COG is beginning to test these patients for the presence of these lesions. In other work performed with colleagues from St Jude Children’s Research hospital, we described the genomic and biochemical landscape of hypodiploid ALL, a highly aggressive form of ALL with poor overall survival.
I also conduct translational studies in juvenile myelomonocytic leukemia and embarked upon research that has resulted in mapping out critical genetic lesions in JMML that are hypothesized to signal through hyperactivation of the Ras pathway, beginning with PTPN11 and recently concluding with the discovery of CBL mutations in JMML. My group described that CBL is a new famililal tumor suppressor gene. Together with my colleagues in the CLIA approved laboratory environment, we offer fee-for –service clinical testing for JMML associated mutations, including PTPN11, NRAS, KRAS, and CBL. We have also harnessed and developed phosphoflow cytometric methods in order to accurately map out perturbed signaling networks in subsets of primary leukemia cells, focusing first on JMML and are currently addressing signaling perturbations in ALL.
I am also keenly interested in developmental therapeutics and have served as Study Chair of a Phase I trial to assess the maximally tolerated dose of the JAK inhibitor, ruxolitinib, in children, in order to build upon laboratory observations that support the use of this compound in specific subsets of leukemia and JMML. Additional work will focus on testing the MEK inhibitor, Trametinib, in cohorts of patients with solid tumors and leukemia.
- Mignon Loh