My lab is investigating the molecular biology of leukemogenesis.  Studies in the laboratory are focused on the molecular alterations in signal transduction and gene expression that are associated with leukemic vs. normal blood cell development.  The goals of the studies in the laboratory are to identify functionally significant molecular abnormalities in leukemia cells in order to target these abnormalities for therapeutic approaches to leukemia.

One set of projects in the lab are focused on understanding the contribution of aberrant expression of HOX genes to leukemogenesis.  Many poor prognosis forms of acute myeloid leukemia (AML) are associated with increased expression of multiple Hox proteins.  Hox proteins are homeodomain transcription factors which are highly conserved from Drosophila to man.  In the laboratory, we have used high through put molecular screening approaches to identify target genes for some of the Hox proteins that are most commonly associated with poor prognosis in AML.  In these studies, we have identified target genes involved in functional myeloid differentiation, growth factor expression and function, protein ubiquitination and apoptosis.  Studies are ongoing for a number of these potentially significant target genes to characterize the impact of the target gene product on blood cell development using molecular biology, cell biology and animal model approaches.

Another set of projects in the laboratory focus on the role of interferon regulatory factors (IRF proteins) on myeloid leukemogenesis.  Decreased expression of IRF proteins has been described in chronic myeloid leukemia (CML), AML and pre-leukemia (or myelodysplastic syndrome).  We have used high through put screening approaches to identify target genes for a key member of this transcription factor family; IRF8/ICSBP.  We have determined that dysregulated expression of a number of these target genes is functionally significant for increased proliferation, differentiation block and apoptosis resistance in myeloid leukemia cells.  These target gene products are being studied in vitro and in vivo, as discussed above.

In additional projects, we are investigating the role of Shp2 protein tyrosine phosphatase in development of AML and myelodysplastic syndrome.  Activity of this PTP is dysregulated in forms of leukemia characterized by activating mutations in growth factor receptors.  Aberrant activity of Shp2-PTP is the focus of biochemical and molecular biology studies in the lab to identify potential therapeutic agents to inhibit this PTP.  We have demonstrated that aberrant Shp2 activity synergizes with either Hox protein overexpression or IRF8/ICSBP deficiency to rapidly produce AML in murine bone marrow transplantation models.  These models will be used to further define the relevant molecular pathways and test potential therapeutic agents.

Selected Publications:

Lu , Y, Goldenberg, I, Bei, L, Andrejic, J, Eklund, E.A.,  HoxA10 represses gene transcription in undifferentiated myeloid cells by interaction with Histone deacetylase 2. (2003) J. Biol. Chem. 278(48):47792-802

Zhu, CL, Saberwal, G, Lu, YF, Platanias, LC., Eklund, E.A., The interferon consensus sequence binding protein (ICSBP) activates transcription of the gene encoding Neurofibromin 1 (NF1). (2004) J. Biol. Chem. 279, 50874-85

Kakar, R, Kautz, B, Eklund, E.A., JAK2 is necessary and sufficient for interferon gamma-induced transcription of the gene encoding gp91^phox.  (2005) J. Leukocyte Biol. 77, 120-7

Bei, L, Lu, YF, Eklund, EA (2005) HoxA9 activates transcription of the gene encoding gp91phox during myeloid differentiation. J. Biol. Chem. 280, 12359-70

Huang, W., Zhu, C., Saberwal, G., Horvath, E., Lindsey, S., Eklund, EA.  Leukemia associated, constitutively active mutants of SHP2 protein tyrosine phosphatase inhibit NF1-transcriptional activation by the interferon consensus sequence binding protein.  (2006)  Mol. and Cell. Biol. 26; 6311-32.

Lindsey, S., Wang, H., Huang, W., Horvath, E., Zhu, C., Eklund, EA. (2007) Activation of SHP2 protein tyrosine phosphatase increases HoxA10-induced repression of the genes encoding gp91phox and p67phox.  J.  Biol. Chem.  282, 2237-49

Huang, W., Horvath, E, Eklund, EA.  (2007) PU.1, IRF2 and ICSBP/IRF8 cooperate to activate NF1-transcription in differentiating myeloid cells. J. Biol. Chem. 282, 6629-43

Wang, H, Lu, YF, Huang, W, Papoutsakis, ET, Fuhrken, P, Eklund, EA.  (2007) HoxA10 activates transcription of the gene encoding Mkp2 in myeloid cells.  J. Biol. Chem. 282, 16164-76

Bei, L, Lu, YF, Bellis, SL, Zhou, W, Horvath, E, Eklund, EA. (2007) Identification of a HoxA10 activation domain necessary for transcription of the gene encoding Beta 3 integrin during myeloid differentiation.  J. Biol. Chem. 282, 16846-59

Huang, W, Zhu, CL, Wang, H, Horvath, E, Eklund, EA. (2008)The Interferon Consensus Sequence Binding Protein (ICSBP/IRF8) represses PTPN13 gene transcription in differentiating myeloid cells. J. Biol. Chem. 283, 7921-35

Konieczna, I, Horvath, E, Wang, H, Lindsey, S, Saberwal, G, Bei, L, Platanias, L, Eklund, EA. (2008) Constitutive activation of SHP2 cooperates with ICSBP-deficiency to accelerate progression to acute myeloid leukemia. J. Clin. Invest. 118:853-867

Wang, H., Lindsey, S, Konieczna, I, Bei, L, Horvath, E, Huang, W, Saberwal, G, Eklund, EA (2009) Constitutively Active SHP2 Cooperates with HoxA10-overexpression to Induce Acute Myeloid Leukemia. J. Biol. Chem. 284, 2549-67

View Publications by Elizabeth Eklund listed in the National Library of Medicine (PubMed).

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