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Segat, Gabriela Cristina

University of British Columbia

Although our understanding of the genetic basis of T-cell acute lymphoblastic leukemia (T-ALL) has improved with next-generation sequencing efforts, features underlying poor outcome remain unclear. To deconvolute the individual contributions of T-ALL oncogenes and generate more relevant experimental models, a recently developed, efficient and reproducible synthetic T-ALL model from primary human CD34+ cord blood cells was used. RNA-seq of synthetic leukemias showed that the same set of genetic alterations can lead to two distinct types of leukemia – one resembling uncommitted T-cell progenitors (Early) and another resembling committed, double positive T cells (Late). Early leukemias exhibited high MYCN expression, which correlated with poor clinical outcome in a large pediatric cohort. Knockout and knockdown experiments revealed Early leukemias to be dependent on MYCN for initial transformation and subsequent clonal propagation. Use of histone ChIP-Seq data revealed broad domains of H3K4 trimethylation extending across the entirety of the MYCN gene body. Knockdown of the lysine methyltransferase KMT2D via shRNA resulted in reduced expression of MYCN and severely restricted growth of Early leukemia cells. These findings suggest a prominent role for epigenetic regulation in maintaining consistent oncogene expression and defining the malignant identity of a particularly aggressive subtype of human leukemia. The fact that the same set of genetic alterations can lead to distinct leukemia subtypes suggested other variables such as cell developmental stage and microenvironment could influence the transformation process. Because adult patients present a worse prognosis in T-ALL and aging is accompanied by a progressive increase in the body’s proinflammatory microenvironment, I then employed our synthetic model to study how chronic inflammation can alter T-cell development and leukemogenesis. I found that chronic inflammatory stimulation delays T-cell differentiation and alters the growth and differentiation trajectory of transformed cells, which ultimately favors selection of more immature T-ALL subtypes. Overall, these studies identified genetic, epigenetic, and environmental features which contribute to the pathogenesis of immature T-ALLs. These results emphasize developmental stage-specific oncogene and cytokine dependencies which could inform the development of new therapeutic options.

Text

2023-10-19

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86229

Interdisciplinary Oncology

University of British Columbia

UBCV

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