Defining Leukemogenic Mechanisms in Hereditary Hematopoietic Malignancies

Hereditary hematopoietic malignancies (HHMs) were once thought to be exceedingly rare, but the development of relatively inexpensive next generation sequencing (NGS) in the early 21st century led to a dramatic increase in the number of recognized HHM syndromes. Now, HHMs are an accepted entity in the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia, and a substantial proportion of individuals are recognized to be at risk for these syndromes. However, a number of knowledge gaps remain in the field. First, no large-scale natural history study has been completed for individuals with HHMs. Second, individuals with HHMs experience up to a 40% lifetime risk for blood cancers such as acute leukemia (AL) and myelodysplastic syndrome (MDS), but the molecular and genetic steps driving leukemogenesis are not well understood. Third, the field's ability to model HHMs has been limited by a lack of high-fidelity models. Finally, many individuals with an HHM phenotype who undergo clinical-grade sequencing do not have a clear germline genetic driver identified, which suggests additional HHMs remain to be discovered. During my doctoral work, I have addressed these knowledge gaps by completing the first large-scale natural history study investigating pre-leukemic states in individuals with germline mutations in DDX41, GATA2, or RUNX1 in collaboration with colleagues from the University of South Australia and the National Institutes of Health. These studies demonstrate that strikingly distinct patterns of leukemogenesis exist among these syndromes. As a component of this work, I drove our group's efforts to generate the largest international genomics database focused on RUNX1 germline mutation carriers, which allows genomics data from disparate sources to be analyzed via a uniform bioinformatics pipeline. I hope that this database will facilitate data sharing in the field of hereditary hematopoietic disorders. I extended this work to perform the largest natural history study investigating leukemogenesis in individuals with a hereditary thrombocytopenia/hereditary hematopoietic malignancy (HT/HHM) phenotype driven by germline mutations in ANKRD26 or ETV6. These two syndromes phenocopy RUNX1 germline mutations, but it was previously unknown how pre-leukemic states differed in these phenocopies as compared to RUNX1 germline mutation carriers. I have also been involved in a study comparing induced pluripotent stem cells (iPSCs) derived from patients with ETV6 or RUNX1 germline mutations, the first of its kind, as well as the first studies characterizing an iPSC line derived from a patient with a germline ANKRD26 mutation. Finally, I have also identified a novel HT/HHM driven by germline mutations in TTLL6 and have investigated the potential role of germline TUBB1 mutations as a novel HT/HHM syndrome. Overall, my results regarding HHMs have generated novel insights into the leukemogenic mechanisms among individuals with HHM-associated germline mutations, have facilitated data sharing and collaboration across international and institutional boundaries, and have generated patient-derived cellular models that may be used for future work investigating mechanisms of disease and novel therapeutic approaches specific to the HHMs.