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T-cell acute lymphoblastic leukemia (T-ALL) is a deadly disease frequently associated with mutations in NOTCH1. Gfi1 is a zinc finger transcriptional repressor protein originally identified in a mouse model of T-ALL. We have recently determined that the most frequently activated gene in MMLV-induced murine T-ALL has a pivotal role in human leukemia. Our data suggest that Gfi1 might be a very important protein for the maintenance of multiple forms of lymphoid malignancies; making Gfi1 a central target for clinical intervention. We have shown that Gfi1 counters p53 activity in transformed lymphocytes (Cancer Cell 2013), and that Gfi1 is required for lymphoid lineage priming of hematopoietic progenitors (PLoS Genetics 2013). Currently, we are defining the transcriptional targets of Gfi1 that make it essential to T-cell development and transformation.
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.
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.
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.
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Project: Gfi1-regulated miR-21 and miR-196b control G-CSF-stimulated neutrophil differentiation.
Cytospin of wt versus miR-21 and miR-196b expressing cells.
Project: Gfi1’s role in lymphoid malignancies.
Recently we showed that the Drosophila orthologs of Gfi1 and HoxA9 bind similar DNA sequences and antagonize target gene regulation (REF Li-Kroeger et al. Dev Cell, PMID: 18694568). In mammals, we showed that Gfi1 regulates HoxA9, Meis1 and Pbx1 during normal myeloid differentiation (REF Horman et al. Blood 2010 PMID: 19346496). This figure shows a schematic representation of Gfi1-HoxA9 competitive binding on an enhancer element leading to different transcriptional outcomes.
Project: Role of microRNA in acute myelogenous leukemia.
Representative image of primary leukemia cells transfected with fluorescent microRNA.
Project: Role of microRNAs in blood stem and progenitor cells.
Role of microRNA in hematopoiesis.
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