Grimes Lab

Gfi1 is a transcriptional repressor that inhibits myeloid progenitor proliferation and instructs granulopoiesis. HoxA9, a member of the homeobox genes, is a transcription factor promoting stem and progenitor cell proliferation. HoxA9 is recurrently found overexpressed in acute myeloid leukemias, resulting from chromosomal translocations such as Nup98-HoxA9 and MLL-AF9. Our lab previously established the antagonistic relationship between Gfi1 and HoxA9. To further explore the role of the Gfi1 / HoxA9 antagonism in stem-progenitor and myeloid cell regulation, we are studying the transcriptome in mice carrying variable alleles of Gfi1 and HoxA9, respectively. Both pre- and post-transcriptional studies, utilizing ChIP-seq and RNA-seq, will help clarify the epistatic relationship of Gfi1 and HoxA9.
 
Project lead: Andre Olsson

Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Recent microarray studies comparing primary human AML patient specimens with common chromosomal translocations (e.g., MLL versus CBF translocations) or other prevalent oncogenic mutations (e.g., FLT3 / ITD) revealed distinct microRNA profiles associated with each group of genetic abnormalities. Given this specificity of microRNA expression for a particular genetic aberration and the recent progress toward targeting microRNAs in cancer therapeutics, we are testing the hypothesis that specific microRNAs associated with a molecular subtype of AML are required for the leukemogenic properties of that particular subtype.

Project lead: Sara Meyer

Gfi1, a transcriptional repressor, is critically required for hematopoietic stem cell (HSC) self-renewal and normal myeloid differentiation. Humans with severe congenital neutropenia (SCN) display mutations in Gfi1 (encoding GFI1N382S), and previous work in our lab has shown that this mutant acts as a dominant negative block to granulopoiesis (Immunity, 2008; PMID:18328744). Gfi1 regulation of HoxA9, Pbx1 and Meis1 underlies these phenomena in that the Gfi1 / Hox transcriptional circuit controls the accumulation of myeloid progenitors in vivo (Blood, 2009; PMID:19346496). Additionally, we have shown that Gfi1 regulates microRNAs (miRs) during myelopoiesis, and that the forced expression of miRs in bone marrow cells results in an accumulation of myeloid progenitors similar to that of Gfi1 (Blood, 2009; PMID: 19278956). We are investigating the role of microRNA targets in stem cells and myeloid biology, as well as investigating whether miRs represent potential therapeutic targets for clinical intervention in diseases such as SCN and leukemia.

Project lead: Chinavenmeni Velu