Graft-versus-host disease is one of the major problems in clinical bone marrow transplantation. Many experiments in animals have shown that it could be greatly reduced if mature T lymphocytes were removed from the donor marrow. Here we describe a new rat monoclonal antibody, CAMPATH 1, which is suitable for depleting lymphocytes from human marrow grafts. CAMPATH 1 is an IgM that fixes human complement. It binds to both T and B lymphocytes and some monocytes but not to other hemopoietic cells. When peripheral blood mononuclear cells were treated with CAMPATH 1 and complement, more than 99% of lymphocytes were killed and viable T cells could no longer be detected. Under these conditions, in vitro multipotential erythroid and myeloid colony-forming cells were unaffected. As well as being used for in vitro treatment of bone marrow to remove T cells, CAMPATH 1 could potentially be applied to other experimental and clinical situations where depletion of lymphoid cells is required, including serotherapy to achieve immunosuppression for organ transplants or to treat lymphocytic leukemias.

A recurrent translocation between chromosome 1 (Pbx1) and 19 (E2A) leading to the expression of the E2A-Pbx1 fusion oncoprotein occurs in ϳ5 to 10% of acute leukemias in humans. It has been proposed that some of the oncogenic potential of E2A-Pbx1 could be mediated through heterocomplex formation with Hox proteins, which are also involved in human and mouse leukemias. To directly test this possibility, mouse bone marrow cells were engineered by retroviral gene transfer to overexpress E2A-Pbx1a together with Hoxa9. The results obtained demonstrated a strong synergistic interaction between E2A-Pbx1a and Hoxa9 in inducing growth factor-independent proliferation of transduced bone marrow cells in vitro and leukemic growth in vivo in only 39 ؎ 2 days. The leukemic blasts which coexpress E2A-Pbx1a and Hoxa9 showed little differentiation and produced cytokines such as interleukin-3, granulocyte colony-stimulating factor, and Steel. Together, these studies demonstrate that the Hoxa9 and E2A-Pbx1a gene products collaborate to produce a highly aggressive acute leukemic disease.

T cell differentiation in the thymus is dependent upon signaling through the TCR and is characterized by the resulting changes in expression patterns of CD4 and CD8 surface coreceptor molecules. Although recent studies have characterized the effects of proximal TCR signaling on T cell differentiation, the downstream integration of these signals remains largely unknown. The growth factor independence-1 (GFI1) and GFI1B transcriptional repressors may regulate cytokine signaling pathways to affect lymphocyte growth and survival. In this study, we show that Gfi1 expression is induced upon induction of the T cell program. Gfi1B expression is low and dynamic during T cell development, but is terminated in mature thymocytes. Transgenic expression of GFI1 and GFI1B in T cells allowed us to determine the functional consequences of constitutive expression. GFI1 potentiates response to TCR stimulation and IL-2, whereas GFI1B-transgenic T cells are defective in T cell activation. Moreover, GFI1B-transgenic thymocytes display reduced expression of the late-activation marker IL-7Rα, and a decrease in CD4−8+ single-positive T cells that can be mitigated by transgenic expression of BCL2 or GFI1. These data show that GFI1 and GFI1B are functionally unique, and implicate a role for GFI1 in the integration of activation and survival signals.

IL-1 is released by activated monocytes and is thought to be a key mediator of the host immune response. The availability of the purified and, more recently, recombinant IL-1 has allowed the characterization of other biological properties of this molecule. Thus, IL-1 is thought to have the same properties as hemopoietic 1, a growth factor that has been shown to act on primitive murine hemopoietic cells. Here we report that rIL-1 acts synergistically with granulocyte/macrophage CSF (GM-CSF) or granulocyte CSF in the stimulation of clonogenic cells from many patients with acute myeloblastic leukemia (AML). Although IL-1 by itself has no effect on AML blasts, it can support colony formation under conditions where there is detectable production of endogenous GM-CSF. IL-1 also promotes the growth of multipotential progenitors from normal human bone marrow cells in the presence of GM-CSF. These observations support the hypothesis that in the hemopoietic system, IL-1 has a selective effect on primitive precursors.

Transgenic mice carrying the v-Ha-ras oncogene under the control of the mouse mammary tumor virus long terminal repeat were produced. These mice exhibit several phenotypes: mammary tumors, bilateral hyperplasia of the harderian lacrimal gland, primary bronchio-alveolar lung adenocarcinoma, and splenomegaly. High levels of the transgene RNA were detected in mammary, harderian, and lung tumors. Accumulation of cells of the myeloid lineages was found in enlarged spleens. This phenotype may represent an indirect effect of v-Ha-ras expression on myeloid progenitors. Our data illustrate the cell-specific effects of v-Ha-ras.The Ha-ras proto-oncogene is a member of a larger family of related proteins (Ras family) which have been frequently found activated in several animal and human tumors and are thought to play an important role in the emergence of these malignancies (34). An activated c-Ha-ras oncogene has been identified repeatedly in mammary carcinoma induced by N-nitroso-N-methylurea and by dimethylbenzanthracene in rats (37) and by dimethylbenzanthracene in mice (5). Similarly, activated c-Ha-ras or K-ras oncogenes have been detected in a number of human breast carcinoma cell lines (17,18,23), and some specific Ha-ras alleles were found at a higher frequency in patients with breast tumor than in normal patients (19). In fact, most human breast carcinoma revealed elevated levels of c-Ha-ras RNA and protein (4, 10, 33). These results suggest a role for this oncogene in the initiation or progression of this malignancy or both.Transgenic mice offer an attractive system to study the effect of an oncogene in a given tissue under normal physiological conditions. To study the role of the activated v-Ha-ras oncogene in the development of mammary tumors, we constructed transgenic mouse lines carrying the v-Ha-ras oncogene under the control of the mouse mammary tumor virus (MMTV) enhancer-promoter.A 4.2-kilobase-pair EcoRI-NcoI fragment containing the MMTV long terminal repeat (LTR) linked to the v-Ha-ras oncogene was purified from pA9 DNA (15) (Fig. 1) and microinjected into the male pronucleus of (C3H x C57BL/6)F2 zygotes (14). Five animals carrying the transgene (founders) were produced. Four transmitted the transgene to their progeny and were bred as lines (designated lines MR2 to MR5) by mating with BALB/c J mice, as this strain is known to be among the most susceptible to MMTV-induced mammary carcinoma.Predominant phenotypes of transgenic mice. Five phenotypes not seen in control mice were observed in the transgenic mice: mammary tumors, exophthalmia, splenomegaly, salivary gland tumors, and lung tumors.