Functionalizing novel PHIP variants in ancestry specific Acute Myeloid Leukemia
Bailee Kain
PhDCincinnati Children's Hospital
Project Term: July 1, 2024 - June 30, 2027
AML risk stratification established by previous studies do not reflect survival outcomes observed in Black patients. Exome sequencing of 100 Black AML patients revealed the novel variants previously not affiliated with AML, including PHIP. Using multiomic patient sample captures and GEMMs, we will functionalize variants in PHIP and assess if they drive leukemogenesis and/or therapy resistance. The overall goal of this work is to implement inclusive genetic assessment tools for AML diagnosis.
Our collaborator AK Eisfeld showed that young leukemia patients of African ancestry have significantly decreased chance of complete remission and survival compared to leukemia patients of European ancestry. This survival disparity persisted despite considering socioeconomic status, access to treatment, follow-up, and age. When the DNA of the leukemias were sequenced, we found patients with African ancestry have mutations in genes not seen in those with European ancestry. We don’t know whether the mutations are the cause of treatment failure. One clue that they might be important comes from the fact that the same genes are mutated in several patients (they are “recurrent”) and present in other human genetic disorders. An example of these novel variants is Pleckstrin-Homology-Domain Interacting Protein (PHIP). PHIP mutations are found at the same rate of other known drivers of blood cancer being investigated as targets for therapeutic intervention. We hypothesize that PHIP mutations are involved in leukemia formation and/or therapy resistance.
To prove that mutations in PHIP might affect leukemia biology, we propose to use multiple experimental tools. We will use European and African ancestry patient bone marrow samples with or without PHIP mutations to rigorously characterize cell populations and gene expression using cutting-edge single cell technologies. We will determine if 1) PHIP mutations cause higher numbers of leukemic stem cells, leading to increased relapse and poor survival 2) if these mutations are causing chemotherapy resistance or 3) the location of the PHIP mutation leads to differences in molecular interactions and downstream therapeutic targets. Next, we will use a published model of human bone marrow generated from pluripotent stem cells to screen recurrent PHIP mutations found in our patient dataset to determine if these mutations make cells more prone to leukemia formation. Finally, we will use mouse models containing well known prognostic indicators of AML treatment response to evaluate how PHIP mutants alter response to therapy agents using in hematology oncology clinics. The result of this work has the potential to make cancer screening panels more inclusive and identify novel AML therapeutic intervention strategies in the clinic.