The question of stemlines in human acute leukemia: Comparison of cells isolated in vitro and in vivo from a patient with acute lymphoblastic leukemia

doi:10.1016/0014-4827(79)90504-4

Experimental Cell Research

Volume 62, Issue 1, September 1970, Pages 5-10

https://doi.org/10.1016/0014-4827(79)90504-4 Get rights and content

Abstract

Mononuclear, lymphoblastoid (CCRF-SB) cells isolated in suspension culture from the peripheral blood buffy coat of a child with acute lymphoblastic leukemia have been non-tumorigenic in untreated neonatal Syrian hamsters. This observation is in contrast to the previously reported serial transplantability of H-SB2, a tumor produced in newborn hamsters by the direct implantation of buffy coat cells from the identical blood specimen. Cells of the CCRF-SB culture are, however, tumorigenic in newborn hamsters treated with anti-hamster thymus lymphocyte serum (ALS). Unlike H-SB2, the tumor (H-SB9) produced in hamsters by implantation of the CCRF-SB cells is dependent upon treatment of the host with ALS for transplantation, does not undergo spontaneous conversion to leukemia in the hamster host, and actively synthesizes human immunoglobulins.

These, together with karyotypic and certain biochemical differences (described elsewhere) raise the possibility of the existence of different “stemlines” in this patient with acute lymphoblastic leukemia. However, the available evidence suggests that only the H-SB2 cell population represents a leukemic “stemline”. The CCRF-SB cell population more closely resembles previously described lymphoid cells derived from the peripheral blood of patients with infectious mononucleosis.

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Although is is well known that the expression of major histocompatibility complex (MHC) antigens on the surface of lymphoblastoid cell lines are cell cycle dependent, the way in which the MHC antigen expression on activated T cells varies with cell cycle phase has not previously been described. Using 11 lymphoblastoid cell lines from malignant and nonmalignant tissues (B cells, T cells, and myeloid cells) and five activated cell lines (two cell lines activated by phytohemagglutinin and three alloreactive T cell clones), MHC antigen expression was quantitatively studied by dual-beam flow cytometry. Correlated measurements of surface antigen quantity (immunofluorescence), DNA content (Hoechst 33342), and cell size (light scatter), unifluenced by induction synchrony and cell fixation, were performed. The data indicated that cell surface antugen quantity and cell surface area demonstrate specific values at each phase of the cell cycle when the cells are in logarithmic growth. Examining cells in logarithmic growth, it was confirmed, for all lymphoblastoid cell lines, that the quantity of MHC antigens on G₂ (S+G₂+M) cells was greater than that on G₁ cells. In addition, it was found by analyzing antigen quantity and surface area, that class I antigen density in the G₂ phase is 17% less than thet in the G₁ phase in leukemic T cell lines, and that both class I and class II antigen densities in the G₂ phase were 21% less than that in the G₁ phase in lymphoblastoid B cell lines. In activated T cells, class I antigen density in the G₂ phase was 11% less than that in the G₁ phase, while class II antigen density in the G₂ phase was 12% greater than that in the G₁. We described four important observations in this report. In both G₁ and G₂ phases, activated T cells express: (1) quantitatively fewer class I antigen that lymphoblastoid B cell lines; (2) similar quantity of class I antigens as that of leukemic T cell lines; and (3) similar quantity of class II antigens as that of lymphase B cell lines. Also, (4) class II antigens are expressed in greater density in the G₂ phase than in the G₁ phase in activated T cells. In contrast, lymphoblastoid B cell lines express greater density of class II antigens in the G₁ phase than in the G₂ phase of the cell cycle. These findings differ from previous reports, suggesting that G₁ phase cells may have a more significant role than G₂ phase cells as target cells for MHC restricted cytotoxic cells.
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We have previously shown that two human T-cell lines (HSB and 8402) derived from patients with childhood T-cell ALL (T-ALL) do not synthesize detectable mRNA for HLA-DRα. The DRα genes in both cell lines are hypermethylated relative to the same genes in T-cell lines infected with human T-cell leukemia virus (HTLV) and derived from patients with adult T-cell leukemia/lymphoma (ATL). These latter cell lines do express HLA-DRα-mRNA, as well as HLA-DR surface antigens. We report here that the genes for HLA class I antigens are also highly methylated in the T-ALL T-cell lines relative to the same genes in the ATL T-cell lines, normal peripheral blood T cells, and autologous normal B-cell lines. In spite of substantial differences in the extent of methylation of class I-related genes, no obvious differences exist among these cell types in their levels of expression of HLA-A and -B antigens. The data clearly indicate, however, that the class I and class II components of the major histocompatability complex are unusually hypermethylated in several T-ALL-derived cell lines, while ATL T-cell lines do not substantially differ in this respect from normal peripheral blood T cells.

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^☆: These studies were supported in part by research grants C-6516 from the National Cancer Institute, and FR-05526 from the Division of Research Facilities and Resources, National Institutes of Health; the Albert and Mary Lasker Foundation, New York; and the Alvan T. and Viola D. Fuller Cancer Research Unit Grant, American Cancer Society (Massachusetts Division), Inc.

¹: G.E.F. holds Research Career Award K6-CA-22, 150 from the National Cancer Institute, National Institutes of Health.

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The question of stemlines in human acute leukemia: Comparison of cells isolated in vitro and in vivo from a patient with acute lymphoblastic leukemia☆

Abstract

Exptl cell res

Cancer res

Cancer res

Cancer res

Cancer res

Cancer res

Cancer