Determining the Effect of Chronic Inflammation on Pre-Leukemic Hematopoiesis
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This study sought to determine the ability of chronic inflammation to drive the development and progression of AML. Reportedly, sequential acquisition of mutations in HSC drives the development of AML. Acquisition of a precursor mutation, such as DNTM3A R882H , results in a pre-leukemic HSC that is capable of clonal expansion. However, a second hit is needed in form of additional genetic lesions or external factors, such as chronic inflammation, to drive carcinogenesis. While the contribution of chronic inflammation to induce carcinogenesis has been extensively studied in solid tumors, little is known in context of myeloid malignancies. Epidemiological studies have reported that patients with chronic inflammatory conditions are at a higher risk of developing AML as compared to the normal population. Our LPS model for inducing chronic inflammation is based on the model described by Esplin et al. in which the mice were exposed to low dose LPS daily for a period of 4 weeks. Our assessments on peripheral blood and bone marrow compartments revealed that chronic exposure to low dose LPS did not affect frequencies of HSPCs, but significantly increased total number of BMNCs in NHD13 competitor transplant mouse model. We were intrigued to evaluate the effects of chronic exposure to low dose LPS in another pre-leukemic model- DNMT3A R882H . The data from in vitro serial replating assay, peripheral blood reconstitution experiments and bone marrow analysis in our DNMT3A R882H transplant mice suggested that the retroviral vector could successfully transduce only the progenitors and could not enter the long term HSCs in the conditions that we provided. We then attempted few modifications to improve the transfection and transduction efficiencies to enhance the quality of transplantation. As a result of this modification, not only did the transfection quality improve, the transduction efficiency also improved remarkably. Future directions: It would be interesting to investigate if chronic inflammation induces the presence of dominant malignant clones that expand at the expense of normal counterparts. Secondly, an alternative model for inflammatory disease that more closely represents the model for AML development in humans could be used. A mouse model of chronic granulomatous disease (CGD) that was developed by targeted disruption of p47 phox could be one such model.