Yu-Hua Song

High expression of EDAG and its significance in AML

1 Beck J, Handgretinger R, Dopfer R, Klingebiel T. Expression of mdr1, mrp, topoisomerase IIa/b and cyclin A in primary or relapsed states of acute lymphoblastic leukemias. Br J Haematol 1995; 89: 356–363. 2 Salmon SE, Dalton WS, Grojan TM. Multidrug resistant myeloma – laboratory and clinical effects of verapamil as a chemosensitizer. Blood 1991; 78: 44–50. 3 Weber D, Dimopoulos M, Sinicrope F, Alexanian R. VADcyclosporine for VAD-resistant myeloma. Leuk Lymphoma 1995; 19: 159–163. 4 Barlogie B, Velasquez WS, Alexanian R, Cabanillas F. Etoposide, dexamethasone, cytarabine and cisplatin in vincristine, doxorubicine and dexamethasone-refractory myeloma. J Clin Oncol 1989; 7: 1514–1517. 5 Singhal S, Metha J, Desikan R, Ayers D, Roberson P, Eddlemon P et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–1571. 6 Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001; 98: 492–494. 7 Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai Y-T et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000; 96: 2943–2950.

Gene transfer of pro-IL-18 and IL-1β converting enzyme cDNA induces potent antitumor effects in L1210 cells

We report in a murine model of acute lymphoid leukemia L1210 the potent antitumor efficiency of a combinatorial delivery of pro-IL-18 gene modified L1210 (Lp18) and IL-1β converting enzyme (ICE) gene modified L1210 (LpICE). Live leukemia cells Lp18 or Lp18 plus LpICE showed apparently reduced leukemogenicity with a survival rate of 40 or 50% at 50 days after intraperitoneal (i.p.) inoculation of a lethal dose of cells, respectively. Combination of Lp18 and LpICE was capable of inhibiting accumulation of bloody ascites, synergistically superior to Lp18 or LpICE alone. All surviving mice were rechallenged with parental L1210 cells at day 50, and all survived up to day 80, suggesting that gene-modified cells induced immune protection. Moreover, NK cytotoxicity and CTL activity were both enhanced in mice injected with Lp18, especially Lp18 plus LpICE. Levels of IFN-γ were not altered significantly by inoculation of Lp18 or Lp18 plus LpICE. Our results demonstrate that IL-18 is a useful candidate gene in gene therapy of lymphoma or lymphoid leukemia, and ex vivo combinatorial delivery of Lp18 plus LpICE either as a single approach or as an adjunct to concomitant radiotherapy or chemotherapy, may be more efficient in a situation of minimal residual disease.

Marked Reduction of LL-37/hCAP-18, an Antimicrobial Peptide, in Patients with Acute Myeloid Leukemia

We detected LL-37/hCAP-18 expression in the peripheral blood smears of 50 healthy donors and 143 patients with various hematological diseases. Compared with that in the healthy donors, expression of the protein in the neutrophils was significantly lower in patients with acute myeloid leukemia (AML), especially those with infection, but no significant difference was detected in messenger RNA level.We did not detect increased LL-37/hCAP-18 protein expression in U937 cells treated with lipopolysaccharide or Staphylococcus aureus Cowan strain. Furthermore, LL-37/hCAP-18 protein production was not restored in differentiated myeloid cell lines NB4 or HL-60 induced by all-trans retinoic acid. LL-37/hCAP-18 has been shown to play a role in host defense, and its deficiency in AML may be one of the explanations for susceptibility to infection among these patients.

Clone and expression of mutant M-CSF and its receptor from human leukemic cell line J6-1

Macrophage colony-stimulating factor (M-CSF) plays important roles in hematopoietic and immunologic systems. Some isoforms or mutations have been demonstrated including membrane-bound and cellular M-CSF, which associated with some leukemia, lymphoma and other solid tumors. We previously reported that the M-CSF-like membrane-associated factor (MAF-J6-1) and its receptor was found from human leukemic cell line J6-1. In this report, the cDNA of MAF-J6-1 and its receptor were cloned. The cDNA sequence of MAF-J6-1 shows a 768bp open reading frame (ORF) with 99.2% homology to m-M-CSF, but six site mutations, including two synonymous mutations and four missense mutations. The cDNA of MAF-J6-1-R has a 2916bp ORF shared 99.6% homology with M-CSF-R, but 13 site mutations, including six synonymous mutations and seven missense mutations. At the same time, a 1662bp mutant s-M-CSF cDNA, which has 10 site mutations including three synonymous mutations and seven missense mutations, was cloned from J6-1 cells. The cDNAs of MAF-J6-1 and MAF-J6-1-R were inserted into a mammalian expression plasmid pTARGET and were expressed in COS-7 cells that demonstrated by their specific MAb. COS-7 cells transfected with MAF-J6-1-R show obvious protein tyrosine kinase (PTK) activity. Our present work shows that MAF-J6-1 and its receptor are mutations of M-CSF and its receptor.