The objectives of this project are to characterize the molecular control of myeloid leukemia cells by first establishing the nature of the specific glycoproteins (colony-stimulating factors, CSFs) controlling cell division and differentiation of normal granulocytes and macrophages, then determining the actions of the CSFs on leukemia cells. We have established that four glycoproteins interact to control normal mouse granulocytes and macrophages: GM-CSF, M-CSF, G-CSF, and MultiCSF (IL-3). All four have been purified to homogeneity in small amounts. cDNAs have been cloned for GM-CSF and Multi-CSF with bacterial expression and the recombinant material has similar in vitro and in vivo properties to the native molecules. We have established that G-CSF can suppress myeloid leukemic cells by enforcing terminal differentiation. Using ?125?I-labeled G-CSF, we have shown that receptor numbers on leukemia cells are similar to those on normal GM precursor cells. Differentiation-unresponsive leukemia cells have been shown to lack membrane receptors for G-CSF. These studies will be extended using radiolabeled GM-CSF, and the genetic elements controlling GM-CSF will be sequenced and analyzed. Amino acid sequence data has been obtained from purified G-CSF and attempts are in progress to clone a cDNA for G-CSF, a first step towards the mass production of G-CSF. (M)

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Walter and Eliza Hall Institute Medical Research
Zip Code
Nicola, Nicos A; Babon, Jeffrey J (2015) Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev 26:533-44
Babon, Jeffrey J; Varghese, Leila N; Nicola, Nicos A (2014) Inhibition of IL-6 family cytokines by SOCS3. Semin Immunol 26:13-9
Babon, Jeffrey J; Lucet, Isabelle S; Murphy, James M et al. (2014) The molecular regulation of Janus kinase (JAK) activation. Biochem J 462:1-13
Kershaw, Nadia J; Laktyushin, Artem; Nicola, Nicos A et al. (2014) Reconstruction of an active SOCS3-based E3 ubiquitin ligase complex in vitro: identification of the active components and JAK2 and gp130 as substrates. Growth Factors 32:1-10
Kedzierski, Lukasz; Linossi, Edmond M; Kolesnik, Tatiana B et al. (2014) Suppressor of cytokine signaling 4 (SOCS4) protects against severe cytokine storm and enhances viral clearance during influenza infection. PLoS Pathog 10:e1004134
Varghese, Leila N; Ungureanu, Daniela; Liau, Nicholas P D et al. (2014) Mechanistic insights into activation and SOCS3-mediated inhibition of myeloproliferative neoplasm-associated JAK2 mutants from biochemical and structural analyses. Biochem J 458:395-405
Linossi, Edmond M; Babon, Jeffrey J; Hilton, Douglas J et al. (2013) Suppression of cytokine signaling: the SOCS perspective. Cytokine Growth Factor Rev 24:241-8
Zhang, Jian-Guo; Nicholson, Sandra E (2013) Detection of endogenous SOCS1 and SOCS3 proteins by immunoprecipitation and Western blot analysis. Methods Mol Biol 967:249-59
Babon, Jeffrey J (2013) Quantitative analysis of JAK binding using isothermal titration calorimetry and surface plasmon resonance. Methods Mol Biol 967:57-67
Kershaw, Nadia J; Murphy, James M; Liau, Nicholas P D et al. (2013) SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nat Struct Mol Biol 20:469-76

Showing the most recent 10 out of 287 publications