DF/HCC Program Affiliation

Member, Leukemia Program
Member, Lung Cancer Program

Research Abstract

Dr. Tenen's laboratory focuses on hematopoiesis and leukemia. The laboratory is interested in isolating and characterizing factors which play a role in the differentiation of hematopoietic stem cells into different specific lineages, with particular focus on myeloid (granulocyte and monocyte) differentiation in normal and leukemic cells. The laboratory has isolated and characterized regulatory elements of genes which are expressed at different stages of myeloid differentiation, including CD34, a stem cell specific gene expressed only in the earliest hematopoietic progenitors. Our current studies are focused on two master transcription factors which are regulators of myeloid development: the Ets factor PU.1, and C/EBP alpha. Our studies have demonstrated a role for PU.1 and C/EBP alpha in the myeloid specific expression of a number of important myeloid genes, including the three myeloid CSF (GM, M, and G) receptors, and expression and knockout studies of PU.1 and C/EBP alpha show they play a major role in development of specific myeloid lineages. Current efforts in the laboratory focus on understanding regulation, signal transduction pathways, and interacting partners of PU.1 and C/EBP alpha. We have now identified mutations and specific abnormalities in expression and function of C/EBP alpha in specific subtypes of myeloid leukemias, and a major effort in our laboratory is now focused on further characterization of the role of C/EBP alpha in leukemogenesis. Other projects directed at leukemogenic mechanisms include models of murine leukemia using inducible expression of translocation fusion proteins, such as the Bcr-Abl protein. Most recently, my laboratory has successfully generated a tetracycline inducible BCR/ABL leukemia model, and we have made transgenic animals using a promoter which expresses in early myeloid cells and skin to express the tetracycline transactivator we used in this inducible model. We are also currently developing inducible Cre recombinase animals to generate disruptions of PU.1 and C/EBP alpha in the adult animal. Our long term goals are to understand the abnormalities seen in acute myelogenous leukemia (AML), in which differentiation of myeloid blasts is blocked, and to use these myeloid promoters as tools to drive lineage and stage specific expression of heterologous genes in recipient ES cells and transgenic mice, as a step toward gene therapy applications. Techniques in the laboratory include analysis of regulation, function, and signaling of transcription factors, transgenic and knockout studies, and gene therapy applications.

Publications

• Mueller BU, Pabst T, Osato M, Asou N, Johansen LM, Minden MD, Behre G, Hiddemann W, Ito Y, Tenen DG. Heterozygous PU.1 mutations are associated with acute myeloid leukemia. Blood 2002 Aug 1; 100(3):998-1007
  PMID: 12130514
• Okuno Y, Iwasaki H, Huettner CS, Radomska HS, Gonzalez DA, Tenen DG, Akashi K. Differential regulation of the human and murine CD34 genes in hematopoietic stem cells. Proc Natl Acad Sci U S A 2002 Apr 30; 99(9):6246-51
  PMID: 11983914
• Halmos B, Huettner CS, Kocher O, Ferenczi K, Karp DD, Tenen DG. Down-regulation and antiproliferative role of C/EBPalpha in lung cancer. Cancer Res 2002 Jan 15; 62(2):528-34
  PMID: 11809705
• Johansen LM, Iwama A, Lodie TA, Sasaki K, Felsher DW, Golub TR, Tenen DG. c-Myc is a critical target for c/EBPalpha in granulopoiesis. Mol Cell Biol 2001 Jun; 21(11):3789-806
  PMID: 11340171
• Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W, Zhang DE, Tenen DG. AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med 2001 Apr; 7(4):444-51
  PMID: 11283671
• Huettner CS, Zhang P, Van Etten RA, Tenen DG. Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nat Genet 2000 Jan; 24(1):57-60
  PMID: 10615128
• Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG. CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol 1998 Jul; 18(7):4301-14
  PMID: 9632814
• Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci U S A 1997 Jan 21; 94(2):569-74
  PMID: 9012825