Loh Lab
The mission of the Loh Laboratory is to improve survival outcomes for children, adolescents and young adults affected by the most aggressive leukemias through the development of novel therapies.
Research Projects
B/myeloid mixed phenotype acute leukemia (B/M MPAL) is an aggressive form of leukemia in which the ZNF384 gene can partner with several key transcription regulators. ZNF384 fusions can also occur in B-lymphoid malignancies and this lineage plasticity may depend on the effects of these fusions on chromatin remodeling in different cellular contexts. We are exploring this hypothesis mechanistically through primary patient xenografts, cell line xenografts and transduced cord blood products.
B/myeloid mixed phenotype acute leukemia (B/M MPAL) is an aggressive form of leukemia in which blast cells display B-cell and myeloid cell antigens. The presence of lymphoid and myeloid antigens creates unique opportunities to design multispecific T-cell engaging proteins (“MTEs”) that will preferentially recognize blast cells displaying both sets of antigens while sparing healthy cells that display only one or the other. In collaboration with Dr. Jim Olson's lab, we have generated preliminary data that demonstrates efficient binding of MTEs with selective killing of dual antigen positive cells and little binding/killing of cell lines that display one or none. The goal is to test the best candidates in xenografted small-animal models. We are also exploring other immunologic ways to specifically treat MPAL, including applying the Co-LOCKR system pioneered by our collaborator, Dr. David Baker at the Institute for Protein Design.
Philadelphia chromosome-positive (Ph+) and Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) with ABL-class fusions are aggressive blood cancers of children and adolescents/young adults (AYAs) driven by gene fusions that are associated with constitutive signaling activation. Predictors of relapse in this disease are lacking, with more than 90% of relapses occurring in patients who respond well with negative minimal residual disease at the end of induction chemotherapy. In this project, we will analyze genomic data from patients enrolled on AALL1631, the largest international trial to enroll pediatric and AYA patients with Ph+ or ABL-class Ph-like (1) to identify additional genetic events that are enriched in patients who relapse and (2) to perform drug screens using engineered cell line and patient-derived xenograft models to identify new therapies for patients with additional relapsed-associated mutations.
In order to move new therapies into patients as quickly as possible, it is frequently critical to have tested agents in relevant pre-clinical models. Establishing a pre-clinical core that is populated with an immunocompromised small-animal model that has been engrafted with primary human tumor cells has been a valuable platform for many investigators. The Preclinical therapeutics core at Seattle Children’s Research Institute is an outgrowth of Seattle Children’s Genomics and Epigenomics Program led by Drs. Rachel Rau, Jay Sarthy and Scott Furlan. Development of the core is supervised by Drs. Shan Lin and Shireen Ganapathi.