Clonal lymphoid progenitor cell lines expressing the BCR/ABL oncogene retain full differentiative function.

Abstract

The early stages of hematopoiesis have been difficult to study due to problems in obtaining homogeneous populations ofprogenitor cells that retain both self-renewal and differentiative capacities. We have developed an in vitro system in which transformation of murine bone-marrow cells with the BCR/ABL oncogene, a gene associated with stem-cell leukemias, leads to the outgrowth of clonal lines that have an early lymphoid progenitor cell phenotype. The progenitor cells retain immunoglobulin heavy and light chain genes in a germ-line configuration. These cells give rise in vitro to pre-B cells that have diverse diversity-joining (D-J) region rearrangements, and on transfer to mice with severe combined immune deficiency, differentiate to surface IgM', immunoglobulinsecreting B cells that respond to T-cell help and function in an antigen-specific fashion. Although their growth is stimulated by BCR/ABL, the progenitor cells depend for continued growth on a stromal cell-derived soluble factor distinct from the pre-B-cell growth factor, interleukin 7.' These fnding show that BCR/ABL can promote proliferation of an early hematopoietic progenitor cell without preventing its differentiation. This system provides a means of studying the complete B-cell developmental process from clonal progenitor cell to end-stage plasma cell.

Expression ofBCR/ABLandBCL-2in myeloid progenitors leads to myeloid leukemias

“…Our results and those of other investigators (34)(35)(36) instead suggest that additional mutations or epigenetic modifications are necessary in BCR͞ABL-positive cells for full transformation. Two studies have reported that 30% (37) and 75% (38) of normal, healthy individuals possessed the t(9;22) translocation in a minority of peripheral blood leukocytes, strongly supporting the notion that BCR͞ABL alone is insufficient for disease development.…”

Systematic identification of type I and type II interferon-induced antiviral factors

“…The tails of the mice were skinned and cultured in DMEM with 10% FBS, 1% (vol/vol) penicillin/streptomycin. Fibroblasts were harvested after 7-10 d. Murine pre-B Cells were derived from bone marrow as described previously (25).…”

Subcellular localization of Bcr, Abl, and Bcr-Abl proteins in normal and leukemic cells and correlation of expression with myeloid differentiation.

“…The oncogenic potential of the Bcr-Abl fusion proteins has been validated by their ability to transform hemopoietic progenitor cells in vitro (10)(11)(12)(13)(14). Furthermore, transgenic mice carrying BCR-ABL constructs develop lymphoid tumors ( 15,16), and reconstituting lethally irradiated mice with bone marrow cells infected with retrovirus carrying the gene encoding p21 BCRABL leads to the development ofseveral fatal hematopoietic neoplasms (17)(18)(19).…”