Studying leukemia with novel patient-derived iPSC-based models
Final Report Abstract
During my time as a postdoctoral fellow at the Icahn School of Medicine at Mount Sinai in the laboratory of Dr. Eirini Papapetrou funded by the DFG, I was able to generate 14 new AML-iPSC lines with different genotypes representing the major groups of AML. The generation of those lines took a very long time. I could also test for of those lines in vivo (2 were already generated beforehand). Until now only one of those lines could engraft into leukemia in mice and further showed a not yet described phenotype. Detailed characterization of this two derived populations within one AML-iPSC line led to the identification of an leukemia stem cell population. I used this line as a unique and new model to study LSCs, which are believed to be the major source of relapse for leukemia patients. This project adds to the efforts of new datasets of transcriptomic and, importantly, chromatin accessibility data and a new gene signature – non-overlapping with previously derived gene sets, including the one from Ng et al. (Ng et al., 2016) – which correlates with patient survival. These datasets can lead to new hypotheses and open new lines of investigation into genes with a role in LSCs. Through integrated genomics analyses of bulk transcriptome and chromatin accessibility data followed by functional validation I found that iLSCs are dependent on RUNX1 activity. I did not find evidence for preferential RUNX1 dependency or lack thereof in association with any specific genetic group. Rather, I detected a higher sensitivity to RUNX1 KD in patient samples enriched for LSCs (higher CD34+ fractions). RUNX1 dependency represents a new vulnerability of AML LSCs with implications for the therapeutic targeting of AML. Furthermore, the LSC-specific RUNX1 target genes that I characterize can provide additional nodes for targeting, leading to new therapeutic opportunities.
Publications
- (2020). Acute Myeloid Leukemia iPSCs Reveal a Role for RUNX1 in the Maintenance of Human Leukemia Stem Cells. Cell Reports 31, 107688
Wesely, J., Kotini, A.G., Izzo, F., Luo, H., Yuan, H., Jun, S., Georgomanoli, M., Zviran, A., Deslauriers, A.G., Dusaj, N., Nimer, S.D., Leslie, C., Landau, D.A., Kharas, M.G. and Papapetrou E.P.
(See online at https://doi.org/10.1016/j.celrep.2020.107688)
