Non-leukemogenic Cells Research Articles

Abstract 1507: Heterogeneity of CD34 and CD38 expression in adult acute B lymphoblastic leukemia cells is reversible and not hierarchically organized

Abstract The existence and identification of leukemia stem cells in adult acute B lymphoblastic leukemia (B-ALL) remain controversial. We examined whether adult B-ALL is hierarchically organized into phenotypically distinct subpopulations of leukemogenic and non-leukemogenic cells or whether most B-ALL cells retain leukemogenic capacity, irrespective of their immunophenotypes. Cells from CD34+CD38-, CD34+CD38+, and CD34-CD38+ subpopulations of primary adult B-ALL xenografts were shown to be capable of reconstituting the original leukemia in NOD-scid-IL2Rg-/- mice. We found that primary leukemia cells from 11 of 25 adult B-ALL patients with different expression profiles of CD34 and CD38 proliferated robustly and became CD34-CD38+ after being co-cultured with OP9 stromal cells. Surprisingly, cultured CD34-CD38+ B-ALL cells were able to reestablish the complete leukemic phenotype in xenografts. Transcriptomic analysis of CD34+CD38-, CD34+CD38+, and CD34-CD38+ fractions purified directly from xenografts and CD34-CD38+ cells from culture revealed no significantly distinct expression profiles of transcription factors among these populations. Furthermore, 5.7% of single adult primary B-ALL cells engrafted in vivo. These observations suggest that adult B-ALL follows the stochastic stem cell model and that the heterogeneity of CD34 and CD38 expression in B-ALL is reversibly dependent on the microenvironment and is not hierarchically organized. Citation Format: Zhiwu Jiang, Manman Deng, Yi Lu, Bing Xu, Peng Li. Heterogeneity of CD34 and CD38 expression in adult acute B lymphoblastic leukemia cells is reversible and not hierarchically organized. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1507. doi:10.1158/1538-7445.AM2015-1507

Leukemia stem cells

Leukemia-initiating cells (LICs) or leukemia stem cells (LSCs) are defined by their ability to form tumors after xenotransplantation in immunodeficient mice and appear to be rare in most human leukemias. In various leukemias, only small subpopulations of cells can transfer disease upon transplantation into immunocompromised NOD/SCID mice, and markers that distinguish the leukemogenic cancer cells from the bulk populations of non-leukemogenic cells have been identified. However, the phenotype of LICs is heterogeneous: it is variable for the different types of acute myeloid leukemias; cells with different membrane phenotype can act as LICs in each B-acute lymphoid leukemia; LICs change during the evolution of chronic myeloid leukemia from the chronic to the acute phase. There is a general consensus that the identification and characterization of leukemic stem cells might lead to the identification of new therapeutic targets and, through this way, to more effective treatments by focusing therapy on the most malignant cells.

Leukemogenesis-associated antigen in HTLV-I-transformed rabbit cells

The presence of a leukemogenesis-associated antigen was investigated in an experimental model of adult T-cell leukemia in (B/J × Chbb:HM)F 1 rabbits, where adult rabbits develop leukemia within 1–2 weeks following inoculation with HTLV-I-transformed syngeneic cell lines. Leukemogenic activity was found in some but not all HTLV-I-transformed cell lines, and was associated with leukocytosis-inducing activity which was assayed by inoculating these cells into adult rabbits of the parental Chbb:HM strain. The leukemogenic cell line diminished or lost the leukemogenic and leukocytosis-inducing activities during prolonged culture in vitro. A mouse mAb was raised which recognized an antigen uniquely expressed on the cell surface of the leukemogenic cell lines. This antigen was present, however, in all HTLV-I-transformed cells examined and the mAb immunoprecipitated the same 65 kD glycoproteins from both leukemogenic and non-leukemogenic cell lines. Taken together, the antigenic epitope seemed to be expressed on the cell surface in such a manner as to be accessible to the mAb in leukemogenic but not non-leukemogenic cells. The analyses of various cell lines revealed that this antigen was an endogenous antigen and not a viral antigen. The antibody was cytotoxic in vitro against leukemogenic cell lines in the presence of complement, and administration of this antibody to leukemic rabbits resulted in an abrupt decrease in the peripheral blood leukocyte number, leading to remission of the disease.

Induction of differentiation of cultured mouse monocytic leukemia cells (Mm-A) by inducers different from those of parent myeloblastic leukemia cells (M1).

Mouse monocytic Mm-A cells are a highly leukemogenic variant line of the monocytic and non-leukemogenic cell line Mm-1, which developed spontaneously from mouse myeloid leukemia M1 cells. Studies were made on whether Mm-A cells could be induced to differentiate further by agents that were effective for inducing differentiation of the parent M1 cells and other leukemic cells. Of the agents tested, butyrate, conditioned medium from concanavalin A-stimulated spleen cells, lipopolysaccharide (LPS) and N6,O2-dibutyryl adenosine 3'5'-cyclic-monophosphate (dbcAMP) significantly stimulated the lysozyme activity of Mm-A cells, which is one of the most characteristic biochemical markers of monocytes and macrophages. Butyrate was the most effective agent for increasing lysozyme production by Mm-A cells; culture with 0.5mM butyrate for 3 days increased lysozyme production by Mm-A cells about 50-fold. Inducers of M1 cell differentiation such as dexamethasone, 1 alpha,25-dihydroxyvitamin D3, arginase, and proteinous inducer did not increase the lysozyme activity. Butyrate also induced NBT reduction and stimulated other differentiation-associated functions, such as expressions of Fc receptors on the cell surface, immune phagocytosis and production of inducer for M1 cell differentiation. Its effect in stimulating differentiation of Mm-A cells was synergistic with that of dbcAMP or LPS. Incubation with butyrate inhibited the proliferation of Mm-A cells, about 0.3mM butyrate causing 50% inhibition. These results indicate that monocytic, leukemogenic Mm-A cells can be induced to differentiate further by butyrate and that the inducers of differentiation of Mm-A cells are markedly different from those of the parent myeloblastic M1 cells.