Infectious Leukemogenesis: Role of Lateral Gene Transfer in Bone Marrow to Create Clonal Diversity in Leukemia Open Access

Lee, Joo Hyun (2015)

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The uncontrolled proliferation of genetically mutated cells is a mechanism for cancer growth and invasion. The accumulation of spontaneous mutations in a malignancy contributes to clonal diversity of cancer derived from a single founding event. We hypothesized that lateral gene transfer between malignant cells and adjacent normal stem cells may provide an alternative mechanism for the accumulation of mutated genes and the multiplicity of distinct clones in leukemia cells. To test this hypothesis we injected C1498 into GFP transgenic murine recipients and cultured leukemia cells (C1498) grown with normal GFP+ (green fluorescent protein). We used in vitro and in vivo model systems to test whether the presence of C1498 induces a survival advantage to GFP+ bone marrow cells. We sorted GFP+ cells from C1498 bearing mice or co-cultures of C1498 with GFP+ bone marrow onto stroma and resorted for GFP+ progeny into secondary, tertiary, and quaternary cultures. Serial transplantation of sorted GFP+ cells from mice initially inoculated with C1498 resulted in an increase, from 1/140 to 1/47, in the precursor frequency of clonogenic GFP+ cells when cells were sorted on to stromal monolayers. The frequency of clonogenic cells progressively increased from 1/170 to 1/54 following co-culture of C4198 with bone marrow from GFP+ mice followed by 5 successive fluorescent activated cell sorting procedures to re-isolate GFP+ cells over a 2 month period. In contrast, parallel experiments sorting GFP+ cells from stromal cultures without C1498 or serial transplantation of GFP+ cells from mice without leukemia cells showed loss of clonogenic activity in vitro after the second sort. These data are consistent with a model in which growth-promoting or transforming genes from leukemia cells become incorporated within a healthy hematopoietic stem or progenitor cell, contributing to the genetic diversity of leukemia through the initiation a new leukemic clone. Genetic analysis must be done to compare the DNA sequences between the parental leukemia cell line, sorted populations of clonogenic GFP+ cells obtained from the in vitro and in vivo experiments and C57BL/6 mice to confirm the transformation of healthy bone marrow hematopoietic stem cells with genetic sequences derived from the leukemia cells.

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