The Steidl Lab
Albert Einstein College of Medicine
(PI: Dr. Ulrich Steidl)
Research InterestsTranscriptional and Epigenetic Regulation of Normal and Cancer Stem Cells in Hematopoiesis and Leukemia
Acute myeloid leukemias (AML) are malignant diseases that originate from a single transformed cell which has progressively acquired critical genetic changes that disrupt key growth-regulatory pathways. Despite the established use and optimization of regimens applying polychemotherapy and the development of multiple new agents that are effective at reducing the tumor burden in patients with leukemia, relapse continues to be the most common cause of death in AML. Newer experimental evidence demonstrates that AML arises from a small population of cancer stem cells / leukemia stem cells (LSC). Similar to normal hematopoietic stem cells (HSC), LSC are quiescent in terms of cell cycle and thus, conventional cytotoxic therapies are not effective against LSC in the majority of cases. However, therapeutic eradication of the LSC within the leukemia clone will be essential for a cure of disease. Therefore, an improved understanding of the molecular pathways that suppress the formation and maintenance of LSC is required for the development of therapies that target LSC rather than the bulk tumor cells (leukemic blasts). Recent findings from our own group and others demonstrate a critical role of transcriptional master regulators (e.g. PU.1) in the genesis and function of LSC in AML, and that transcription factors are already deregulated in the early stem cell compartment. The goal of our research is to identify critical mechanisms that drive leukemia stem cell (LSC) development and function, and to better understand the mechanisms of how transcriptional regulators (e.g. transcription factors and chromatin-remodeling factors) cause formation of LSC. To identify implicated pathways we are utilizing rigorously defined stem and progenitor cell subsets isolated by means of multi-parameter high-speed fluorescence-activated cell sorting. Identified target genes are biochemically and functionally tested using lentiviral gene transfer and in vitro as well as in vivo assays for leukemia stem cell self-renewal and differentiation, including colony-forming assays, serial replating assays, and Selected publications: Will et al., Blood 2009; 114(18):3899-908 Effect of the nonpeptide thrombopoietin receptor agonist eltrombopag on bone marrow cell from patienst with acute myeloid leukemia and myelodysplastic syndrome. [ PDF ] Thrombocytopenia is a frequent symptom and clinical challenge in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Eltrombopag is a small molecule thrombopoietin receptor agonist that might be a new option to treat thrombocytopenia in these diseases, provided that it does not stimulate malignant hematopoiesis. In this work, we studied the effects of Eltrombopag on proliferation, apoptosis, differentiation, colony formation, and malignant self-renewal of bone marrow mononuclear cells of patients with AML and MDS. Malignant bone marrow mononuclear cells did not show increased proliferation, or increased clonogenic capacity at concentrations of Eltrombopag ranging from 0.1 to 30 microg/mL. On the contrary, we observed a moderate, statistically nonsignificant (P = .18), decrease of numbers of malignant cells (mean, 56%; SD, 28%). Eltrombopag neither led to increased 5-bromo-2-deoxyuridine incorporation, decreased apoptosis, an increase of malignant self-renewal, nor enhanced in vivo engraftment in xenotransplantations. Furthermore, we found that Eltrombopag was capable of increasing megakaryocytic differentiation and formation of normal megakaryocytic colonies in patients with AML and MDS. These results provide a preclinical rationale for further testing of Eltrombopag for treatment of thrombocytopenia in AML and MDS. Steidl et al., J Clin Invest 2007; 117:2611-20 A distal single nucleotide polymorphisms alters long-range regulation of the PU.1 gene in acute myeloid leukemia Targeted disruption of a highly conserved distal enhancer reduces expression of the PU.1 transcription factor by 80% and leads to acute myeloid leukemia (AML) with frequent cytogenetic aberrations in mice. Here we identify a SNP within this element in humans that is more frequent in AML with a complex karyotype, leads to decreased enhancer activity, and reduces PU.1 expression in myeloid progenitors in a development-dependent manner. This SNP inhibits binding of the chromatin-remodeling transcriptional regulator special AT-rich sequence binding protein 1 (SATB1). Overexpression of SATB1 increased PU.1 expression, and siRNA inhibition of SATB1 downregulated PU.1 expression. Targeted disruption of the distal enhancer led to a loss of regulation of PU.1 by SATB1. Interestingly, disruption of SATB1 in mice led to a selective decrease of PU.1 RNA in specific progenitor types (granulocyte-macrophage and megakaryocyte-erythrocyte progenitors) and a similar effect was observed in AML samples harboring this SNP. Thus we have identified a SNP within a distal enhancer that is associated with a subtype of leukemia and exerts a deleterious effect through remote transcriptional dysregulation in specific progenitor subtypes.Steidl et al., Nat Genet 2006; 38:1269-77 Essential role of Jun family transcription factors in PU.1 knockdown-induced acute myeloid leukemia Contact Details:Ulrich G. Steidl Tel. (Office): (718) 430-3437 |
