Showing papers by "Andreas Strasser published in 1989"

One synchronous wave of B cell development in mouse fetal liver changes at day 16 of gestation from dependence to independence of a stromal cell environment.

Abstract: Precursor cells of the B lineage can be enriched from mouse fetal liver by FACS with the aid of the pre-B cell-specific mAb G-5-2. The cells are concomitantly enriched for cells expressing the pre-B cell-specific gene lambda 5, and for cells developing to LPS-reactive mature B cells. The enriched purified precursors are not influenced by rIL-2 through -7, alone or in combination, to develop to mitogen-reactive, sIg+ cells. Marginal proliferation of the precursors is observed in response to IL-3 plus -4, and IL-6 plus -7, and this does not change in the presence of stromal cells. Development to mitogen-reactive, sIg+ cells is dependent on interactions with embryonic stromal cells from fetal liver. Two mAbs raised against the stromal cells inhibit this development. Two phases of precursor cell development can be distinguished in fetal liver. Between days 13 and 15 of gestation, it is dependent on stromal cell interactions, thereafter, from days 16 to 19, it is independent. A sudden increase in the number of mitogen-reactive, sIg+ B lineage cells occurs within 24 h between days 16 and 17. All these results indicate that B cell development occurs in one wave with synchronous steps of changes from a mitogen-insensitive, sIg-, stromal cell dependent to a mitogen-reactive, sIg+, stromal cell-independent B lineage line.

Cellular Stages and Molecular Steps of Murine B-cell Development

Abstract: Development of B cells in fetal liver occurs in one synchronous wave and involves probably no more than four critical divisions. This leads us to suggest that the main pool of proliferating progenitors that replenish the peripheral B-cell pool are progenitors before Ig gene rearrangement, that the four Ig gene rearrangements (DH to JH, VH to DHJH, VK to JK, and V lambda to J lambda) might occur in four critical divisions, and that a stromal-cell-dependent phase of pre-B development in which all rearrangements are made is succeeded by a stromal-cell-independent phase of sIG+ pre-B-cell maturation to mature mitogen-reactive B cells. We speculate on the molecular nature of the tightly controlled steps of Ig rearrangements during pre-B-cell development that might involve the pre-B-cell specific genes Vpre-B and lambda 5 and the B-lineage-specific gene mb-1 in interactions with stromal cells.

The transgenic window on lymphoid malignancy.

Abstract: Transgenic mice bearing an oncogene targetted for expression in a specific tissue can reveal how that oncogene influences differentiation and help to delineate the pathways to malignancy. To explore lymphoid neoplasia, we have made strains of transgenic mice bearing different oncogenes driven by the immunoglobulin heavy chain enhancer (E mu), which promotes expression within lymphocytes and certain myeloid cells. The prototype E mu-myc mice succumb to pre-B and B cell lymphomas, following a preneoplastic phase in which cycling pre-B cells are overproduced. The similar fate of E mu-N-myc mice suggests that N-myc and myc have overlapping functions. Surprisingly, E mu-N-ras mice develop T lymphomas and macrophage tumours but no B lineage tumours; thus the ability of ras to initiate tumorigenesis may be lineage specific. Similarly, the high predisposition of E mu-v-abl mice to develop plasmacytomas may indicate that v-abl is oncogenic only at certain stages of B cell maturation. The bcl-2 gene promotes cell survival rather than proliferation, and E mu-bcl-2 mice produce copious resting B lymphocytes. The random onset and monoclonality of tumours in the transgenic strains argues for spontaneous genetic alterations that cooperate with the trans-oncogene. Indeed, most plasmacytomas of E mu-v-abl mice bear spontaneous myc rearrangements. Moreover, a minority of E mu-myc B lymphomas exhibit ras mutation, and the tumorigenesis can be reconstructed by crossing E mu-myc and E mu-ras mice, or by retroviral delivery of v-ras or v-raf, either in vitro or in vivo. To access novel cooperating oncogenes, we are using a retrovirus lacking an oncogene as an insertional mutagen. This approach should be applicable to any trans-oncogenic strain and help to delineate the genetic events that trigger malignant clones.

Precursor B lymphocytes--specific monoclonal antibodies and genes.

Abstract: The pool of mature, surface immunoglobulin (Ig) positive, antigen-sensitive B cells of a mouse has been estimated to contain 5 × 108 to 109 cells (Osmond 1986). Development from pluripotent stem cells and committed progenitors generates daily some 5 × 107 cells, of which 3 × 106 enter the pool of mature B cells. The same number of mature B cells must consequently die daily to keep the pool at a constant size. The immediate precursors of the mature B cells, called pre B cells, can be identified to be at various stages of their development by the genomic context in which their Ig gene loci are found. Thus, rearrangement of a DH to a JH segment on the Ig heavy (H) chain locus precedes that of VH to DHJH. This, in turn, is followed by rearrangements of the Igk light (L) chain and, finally, of the λ L chain locus (Tonegawa, 1983). No more than five divisions are estimated to occur from the earliest (i.e. at the time of DH to JH rearrangement) to the latest (i.e. at the time of surface Ig expression) state of their B lineage development in either fetal liver during embryogenesis or in bone marrow throughout adult life. The daily generation of 5 × 107 cells must, therefore, be fed from more than 106 B-lineage-committed progenitors and from stem cells. Very little is known of the forces that drive this early expansion of cells towards the B lineage, which should be antigen-independent, polyclonal and self-renewing, and might occur in fetal liver and bone marrow in contact with stromal cells.