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Analysis of a de novo c-MYC-induced model of human acute myeloid leukemia

University of British Columbia

Human acute myeloid leukemias (AMLs) are a genetically and biologically diverse group of clonal hematologic malignancies in which abnormally differentiated hematopoietic cells expand excessively and are often characterized by MYC transcription factor overexpression. Current evidence suggests that the acquisition of genetic and epigenetic abnormalities by hematopoietic cells drives the disease. However, it is not known whether these genetic insults alone are sufficient for AML initiation, or from which cell types within the hematopoietic hierarchy the expansion of a leukemic clone can be initiated. To investigate these questions, I first undertook experiments to determine if it would be possible to initiate a leukemia from normal human CD34+ hematopoietic cells forced to overexpress MYC. Initial results showed their transplantation into immunodeficient mice genetically engineered to express human IL3, GM-CSF and SCF growth factors (GFs) resulted in the production of a rapidly fatal AML population, but this did not occur in hosts that did not express these human GFs. In fact, in mice not producing these GFs, the same MYC-transduced cells produced a normal spectrum of differentiating hematopoietic cell types for months. However, upon transfer into secondary GF-producing hosts, they rapidly initiated AML, demonstrating a critical role of these GFs in forcing the activation of a leukemogenic program long after expression of the oncogenic driver was initiated. Transplantation of MYC-transduced cells co-transduced with IL3 or GM-CSF or SCF individually into non-GF mice revealed IL3 and GM-CSF to have equivalent and exclusive AML-activating activity. Transplantation of GF-producing mice with different subsets of MYC-transduced CD34+ cells showed serially transplantable AML populations could be obtained at high efficiency from both primitive (CD34+CD38-) and mature granulopoietic progenitor cells (GMPs). Preliminary analysis of their properties further showed their cell surface phenotypes, transcriptomes, GF-dependence and content of in vitro clonogenic cells to be indistinguishable, and most like normal GMPs amongst different subsets of normal cord blood CD34+ cells. These results indicate that extrinsically-derived immunomodulatory signals can have an important role in eliciting a leukemogenic potential in human cells, and thus lay a foundation for improved understanding of the mechanisms involved in the establishment of human AML.

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2020-06-16

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/74707

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/