Our laboratory works in the fields of hematopoiesis, molecular biology, and molecular oncology including mouse modeling of hematopoiesis, myelopoiesis and leukemia. Our work on the Growth factor independent-1 (Gfi1) transcriptional repressor protein has spanned the initial identification of Gfi1 in a mouse model of leukemia and the role of Gfi1 in normal myeloid biology, to the identification of GFI1 mutations in patients with severe congenital neutropenia (SCN). We have identified Csf1, miR-21 and miR-196b as functional targets of Gfi1 that control the SCN-associated Gfi1-mutant block to granulopoiesis. Recently, we have illustrated an ancient Gfi1 versus HoxA9-Pbx1-Meis1 transcriptional circuit present from Drosophila anterior-posterior development to myeloid progenitor maintenance and transformation. Notably, HoxA9, Meis1 and Pbx1 are three key factors widely acknowledged to drive acute myeloid leukemia; however, their critical target genes are relatively obscure. We are now focused on the antagonism between Gfi1 and the HoxA9-Pbx1-Meis1 oncoproteins in myeloid progenitors, where we find that they fight over the regulation of miR-21 and miR-196b. These miR are critically required for Hox-based myeloid transformation. Our latest data provide evidence for an RNA therapeutic modality that efficiently and specifically interferes with miR-21 and miR-196b function in vivo, resulting in significant changes in the survival of mice bearing Hox-based leukemias. Finally, we are also dissecting the role of Gfi1 in controlling the normal process of granulopoiesis.

Research Grants and Contracts

  • R01CA159845 Grimes (PI) (2011-2016), “microRNA in Acute Myeloid Leukemia”
  • Children’s Leukemia Research Association (2012-2013), “Targeting Oncorequisite Factors in Leukemia”
  • Leukemia and Lymphoma Society of America Translational Research Award (2012-2015), “RNA Therapeutics for Leukemia”