Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 Mar;87(5):1908–1912. doi: 10.1073/pnas.87.5.1908

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

P A Scherle 1, K Dorshkind 1, O N Witte 1
PMCID: PMC53593  PMID: 2408044

Abstract

The early stages of hematopoiesis have been difficult to study due to problems in obtaining homogeneous populations of progenitor 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+, immunoglobulin-secreting 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 findings 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.

Full text

PDF
1908

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Altiok E., Klein G., Zech L., Uno M., Henriksson B. E., Battat S., Ono Y., Ernberg I. Epstein-Barr virus-transformed pro-B cells are prone to illegitimate recombination between the switch region of the mu chain gene and other chromosomes. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6333–6337. doi: 10.1073/pnas.86.16.6333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bazill G. W., Haynes M., Garland J., Dexter T. M. Characterization and partial purification of a haemopoietic cell growth factor in WEHI-3 cell conditioned medium. Biochem J. 1983 Mar 15;210(3):747–759. doi: 10.1042/bj2100747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bosma G. C., Custer R. P., Bosma M. J. A severe combined immunodeficiency mutation in the mouse. Nature. 1983 Feb 10;301(5900):527–530. doi: 10.1038/301527a0. [DOI] [PubMed] [Google Scholar]
  4. Champlin R. E., Golde D. W. Chronic myelogenous leukemia: recent advances. Blood. 1985 May;65(5):1039–1047. [PubMed] [Google Scholar]
  5. Coffman R. L. Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development. Immunol Rev. 1982;69:5–23. doi: 10.1111/j.1600-065x.1983.tb00446.x. [DOI] [PubMed] [Google Scholar]
  6. Collins L. S., Dorshkind K. A stromal cell line from myeloid long-term bone marrow cultures can support myelopoiesis and B lymphopoiesis. J Immunol. 1987 Feb 15;138(4):1082–1087. [PubMed] [Google Scholar]
  7. Davidson W. F., Fredrickson T. N., Rudikoff E. K., Coffman R. L., Hartley J. W., Morse H. C., 3rd A unique series of lymphomas related to the Ly-1+ lineage of B lymphocyte differentiation. J Immunol. 1984 Aug;133(2):744–753. [PubMed] [Google Scholar]
  8. Denis K. A., Dorshkind K., Witte O. N. Regulated progression of B lymphocyte differentiation from cultured fetal liver. J Exp Med. 1987 Aug 1;166(2):391–403. doi: 10.1084/jem.166.2.391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dorshkind K., Denis K. A., Witte O. N. Lymphoid bone marrow cultures can reconstitute heterogeneous B and T cell-dependent responses in severe combined immunodeficient mice. J Immunol. 1986 Dec 1;137(11):3457–3463. [PubMed] [Google Scholar]
  10. Early P., Huang H., Davis M., Calame K., Hood L. An immunoglobulin heavy chain variable region gene is generated from three segments of DNA: VH, D and JH. Cell. 1980 Apr;19(4):981–992. doi: 10.1016/0092-8674(80)90089-6. [DOI] [PubMed] [Google Scholar]
  11. Fulop G. M., Phillips R. A. Full reconstitution of the immune deficiency in scid mice with normal stem cells requires low-dose irradiation of the recipients. J Immunol. 1986 Jun 15;136(12):4438–4443. [PubMed] [Google Scholar]
  12. Graf T. Leukemia as a multistep process: studies with avian retroviruses containing two oncogenes. Leukemia. 1988 Mar;2(3):127–131. [PubMed] [Google Scholar]
  13. Kahn P., Frykberg L., Brady C., Stanley I., Beug H., Vennström B., Graf T. v-erbA cooperates with sarcoma oncogenes in leukemic cell transformation. Cell. 1986 May 9;45(3):349–356. doi: 10.1016/0092-8674(86)90320-x. [DOI] [PubMed] [Google Scholar]
  14. Konopka J. B., Watanabe S. M., Witte O. N. An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell. 1984 Jul;37(3):1035–1042. doi: 10.1016/0092-8674(84)90438-0. [DOI] [PubMed] [Google Scholar]
  15. Lee G., Namen A. E., Gillis S., Ellingsworth L. R., Kincade P. W. Normal B cell precursors responsive to recombinant murine IL-7 and inhibition of IL-7 activity by transforming growth factor-beta. J Immunol. 1989 Jun 1;142(11):3875–3883. [PubMed] [Google Scholar]
  16. McKearn J. P., McCubrey J., Fagg B. Enrichment of hematopoietic precursor cells and cloning of multipotential B-lymphocyte precursors. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7414–7418. doi: 10.1073/pnas.82.21.7414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. McLaughlin J., Chianese E., Witte O. N. In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6558–6562. doi: 10.1073/pnas.84.18.6558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Muller-Sieburg C. E., Whitlock C. A., Weissman I. L. Isolation of two early B lymphocyte progenitors from mouse marrow: a committed pre-pre-B cell and a clonogenic Thy-1-lo hematopoietic stem cell. Cell. 1986 Feb 28;44(4):653–662. doi: 10.1016/0092-8674(86)90274-6. [DOI] [PubMed] [Google Scholar]
  19. Namen A. E., Lupton S., Hjerrild K., Wignall J., Mochizuki D. Y., Schmierer A., Mosley B., March C. J., Urdal D., Gillis S. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature. 1988 Jun 9;333(6173):571–573. doi: 10.1038/333571a0. [DOI] [PubMed] [Google Scholar]
  20. Nottenburg C., Weissman I. L. Cmu gene rearrangement of mouse immunoglobulin genes in normal B cells occurs on both the expressed and nonexpressed chromosomes. Proc Natl Acad Sci U S A. 1981 Jan;78(1):484–488. doi: 10.1073/pnas.78.1.484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Palacios R., Karasuyama H., Rolink A. Ly1+ PRO-B lymphocyte clones. Phenotype, growth requirements and differentiation in vitro and in vivo. EMBO J. 1987 Dec 1;6(12):3687–3693. doi: 10.1002/j.1460-2075.1987.tb02702.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pendergast A. M., Clark R., Kawasaki E. S., McCormick F. P., Witte O. N. Baculovirus expression of functional P210 BCR-ABL oncogene product. Oncogene. 1989 Jun;4(6):759–766. [PubMed] [Google Scholar]
  23. Peschel C., Green I., Paul W. E. Preferential proliferation of immature B lineage cells in long-term stromal cell-dependent cultures with IL-4. J Immunol. 1989 Mar 1;142(5):1558–1568. [PubMed] [Google Scholar]
  24. Pierce J. H., Aaronson S. A., Anderson S. M. Hematopoietic cell transformation by a murine recombinant retrovirus containing the src gene of Rous sarcoma virus. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2374–2378. doi: 10.1073/pnas.81.8.2374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pierce J. H., Aaronson S. A. BALB- and Harvey-murine sarcoma virus transformation of a novel lymphoid progenitor cell. J Exp Med. 1982 Sep 1;156(3):873–887. doi: 10.1084/jem.156.3.873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rosenberg N., Witte O. N. The viral and cellular forms of the Abelson (abl) oncogene. Adv Virus Res. 1988;35:39–81. doi: 10.1016/s0065-3527(08)60708-3. [DOI] [PubMed] [Google Scholar]
  27. Schwartz R. C., Stanton L. W., Riley S. C., Marcu K. B., Witte O. N. Synergism of v-myc and v-Ha-ras in the in vitro neoplastic progression of murine lymphoid cells. Mol Cell Biol. 1986 Sep;6(9):3221–3231. doi: 10.1128/mcb.6.9.3221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sharon R., McMaster P. R., Kask A. M., Owens J. D., Paul W. E. DNP-Lys-ficoll: a T-independent antigen which elicits both IgM and IgG anti-DNP antibody-secreting cells. J Immunol. 1975 May;114(5):1585–1589. [PubMed] [Google Scholar]
  29. Spangrude G. J., Heimfeld S., Weissman I. L. Purification and characterization of mouse hematopoietic stem cells. Science. 1988 Jul 1;241(4861):58–62. doi: 10.1126/science.2898810. [DOI] [PubMed] [Google Scholar]
  30. Sudo T., Ito M., Ogawa Y., Iizuka M., Kodama H., Kunisada T., Hayashi S., Ogawa M., Sakai K., Nishikawa S. Interleukin 7 production and function in stromal cell-dependent B cell development. J Exp Med. 1989 Jul 1;170(1):333–338. doi: 10.1084/jem.170.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Takebe Y., Seiki M., Fujisawa J., Hoy P., Yokota K., Arai K., Yoshida M., Arai N. SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1988 Jan;8(1):466–472. doi: 10.1128/mcb.8.1.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tidmarsh G. F., Heimfeld S., Whitlock C. A., Weissman I. L., Müller-Sieburg C. E. Identification of a novel bone marrow-derived B-cell progenitor population that coexpresses B220 and Thy-1 and is highly enriched for Abelson leukemia virus targets. Mol Cell Biol. 1989 Jun;9(6):2665–2671. doi: 10.1128/mcb.9.6.2665. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  33. Till J. E., McCulloch E. A. Hemopoietic stem cell differentiation. Biochim Biophys Acta. 1980 Nov 26;605(4):431–459. doi: 10.1016/0304-419x(80)90009-8. [DOI] [PubMed] [Google Scholar]
  34. Wendling F., Vigon I., Souyri M., Tambourin P. Myeloid progenitor cells transformed by the myeloproliferative leukemia virus proliferate and differentiate in vitro without the addition of growth factors. Leukemia. 1989 Jul;3(7):475–480. [PubMed] [Google Scholar]
  35. Whitlock C. A., Witte O. N. Abelson virus-infected cells can exhibit restricted in vitro growth and low oncogenic potential. J Virol. 1981 Nov;40(2):577–584. doi: 10.1128/jvi.40.2.577-584.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Whitlock C. A., Witte O. N. Long-term culture of B lymphocytes and their precursors from murine bone marrow. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3608–3612. doi: 10.1073/pnas.79.11.3608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Whitlock C. A., Ziegler S. F., Treiman L. J., Stafford J. I., Witte O. N. Differentiation of cloned populations of immature B cells after transformation with Abelson murine leukemia virus. Cell. 1983 Mar;32(3):903–911. doi: 10.1016/0092-8674(83)90075-2. [DOI] [PubMed] [Google Scholar]
  38. Yancopoulos G. D., Alt F. W. Regulation of the assembly and expression of variable-region genes. Annu Rev Immunol. 1986;4:339–368. doi: 10.1146/annurev.iy.04.040186.002011. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES