In vitro growth characteristics of human lymphoid malignancies in primary cell culture

The experimental work presented in this thesis deals with the analysis of the in vitro growth and differentiation characteristics of acute lymphoblastic leukemia ( T end non-T), T cell non Hodgkin's lymphoma and B cell chronic lymphocytic leukemia in primary cell culture. For these studies, reproducible cell culture assays for the growth of these lymphoid tumours first needed to be developed. Considerable attention has been paid to the response of these neoplasms to the polypeptide hormone interleukin 2. The experiments described in chapters 2 and 3 deal with the in vitro colony growth of non-T acute lymphoblastic leukemia (ALL) and with the effect of interleukin 2 on these cells in combination with a factor elaborated by feeder leukocytes. The requirements of the ALL cells for activation with a lectin (PHA) or a phorbol ester (TPA) for colony growth have also been investigated. To assess whether non-T ALL cells differentiate toward more mature cell types during in vitro growth, the morphological and immunological phenotypes of colony cells were determined. To compare the differentiation capacities of ALL with those of acute leukemia of the myeloid differentiation lineage (AML) the abilities of AML to produce more mature progeny under comparable in vitro conditions were studied (chapter 4). Chapter 5 deals with an analysis of growth requirements of 8 cell type chronic lymphocytic leukemia (CLL) in colony culture and specifically with the role of IL2 in the proliferation of B CLL cells. This analysis is extended in chapter 6, in which the results of binding experiments with radiolabeled IL2 are presented. These experiments were carried out to determine numbers and affinity of IL2 receptors expressed by B CLL cells- In addition, the hypothesis that certain CLL cells might be capable of self-stimulation via the autocrine production of IL2 is approached in this chapter. In chapter 7, culture characteristics of acute lymphoblastic leukemia and non Hodgkin's lymphoma (NHL) of the T cell differentiation lineage are presented. The studies described in chapter 8 are our first attempts toward the characterization of membrane phenotypes and growth requirements of normal T -lymphocytic precursor cells in the human bone marrow. For this purpose, we applied the human long-term bone marrow culture system. Knowledge of the growth end differentiation features of normal lymphoid progenitors is essential for our understanding of whether or how the leukemic counter parts of these cells reflect a modified response to growth and differentiation stimuli. In chapter 9 a brief overview of our current understanding of the role of IL2 in the proliferation of neoplastic T and B cells is presented. Moreover, the results of this thesis are discussed in this chapter with reference to their implications for our insight into the control of proliferation and differentiation of the different types of lymphoid leukemia/lymphoma