Uncovering therapeutic vulnerabilities in AML through mechanistic interrogation of MECOM activity

Project summary Despite recent progress in the understanding of the biological underpinnings of acute myeloid leukemia (AML) and advances in the treatment of patients with AML, fewer than one third of patients achieve a durable cure. Therefore, deeper mechanistic insights into the drivers of AML that will lead to adjunctive, targeted therapies is

desperately needed. Recently, I elucidated a gene expression network regulated by the transcription factor MECOM that is essential for hematopoietic stem cell maintenance and that is hijacked in high-risk AML, but the transcriptional and epigenetic co-regulators and essential downstream effectors of the MECOM network are

unknown. In this proposal, I will test the hypothesis that MECOM directly regulates a select group of genes by modulating critical epigenetic pathways, and a subset of those MECOM target genes is essential for AML maintenance. I will test this through a set of two independent specific aims. I seek to 1) mechanistically define

essential co-regulators and direct targets of MECOM activity in maintaining AML progenitors, and 2) identify indispensable downstream effectors of MECOM to uncover therapeutic vulnerabilities in AML. I am an Instructor in Pediatric Oncology with at least 80% protected research time, seeking to apply insights from

stem cell biology to uncover and target essential pathways in AML. My career goal is to become an independent physician-scientist studying transcriptional dysregulation in leukemia, and the purpose of this career development award is to supplement my expertise in stem cell biology with rigorous training in in vivo modeling

of leukemia, and computational analysis. I have an outstanding mentorship team of Drs. Vijay Sankaran and Scott Armstrong who have established track records of high impact scientific output and exemplary mentorship of trainees, and who offer highly complementary areas of expertise. Dr. Sankaran is an innovator and leader in

modeling genetic variation in hematopoietic differentiation and stem cell maintenance, and Dr. Armstrong is an authority on developmental gene expression programs in AML. My advisory committee and collaborators include experts reflecting key areas of my training plan: Drs. Kim Stegmaier (AML genomics), Stu Orkin (hematopoietic

regulation), Manuel Garber (bioinformatics), Anders Hansen (chromatic biology), Seth Goldman (transcriptomics), and Mark Minden (AML). My mentor, co-mentor, advisors, and institution are committed to my research training, career development and progression into an independent physician-scientists at the

conclusion of this award. I will conduct this work at the world-class institutions Boston Children’s Hospital, the Dana-Farber Cancer Institute, and the Broad Institute that will provide an environment of scientific rigor and exceptional mentorship. With the mentored research and career development offered through this K08 award, I

will be ideally suited to establish my independent career as a physician-scientist in pediatric oncology.