Málstofa Lífvísindaseturs - Cohesin haploinsufficiency in Down syndrome leukemia

Málstofa Lífvísindaseturs fimmtudaginn 16. apríl kl. 12:00-13:00 í Árnagarði, stofu 306.

Fyrirlesari: Dr. Halla Rós Eyjólfsdóttir, nýdoktor frá University of New South Wales, Sydney, Ástralíu

Titill: Cohesin haploinsufficiency activates RUNX1 mediated PI3K/Akt/Wnt signaling and aerobic glycolysis in Down syndrome acute megakaryoblastic leukemia

Ágrip: Concurrence of trisomy 21 (T21), GATA1s and cohesin haploinsufficiency is known to be sufficient to drive a Down syndrome acute megakaryoblastic leukemia (DS-AMKL) like phenotype. Which dosage sensitive genes on chromosome 21 (chr21) play a part and their mechanism in this progression has been unexplained thus far. Comparison of our cohesin haploinsufficient RAD21+/- generated DS-AMKL cell line models to the WT RAD21+/+ parental line showed increased protein expression of hematopoietic transcription factors (TFs) GATA1s and FLI1 as well as the chr21 TFs RUNX1, ERG and ETS2 and resulted in dozens to thousands of new and depleted binding sites for these TFs and H3K27ac marks across the genome. The increased expression of GATA1s and FLI1 in K4 and K22 and RUNX1 in K4 but not ERG was shown to be at least partially caused by the PRC1 polycomb complex which is known to differentially modulate chromatin 3D structure in cohesin deficiency. Maturation defects were observed such as reduced ability to mature into large multinucleated megakaryoblasts and CD34 expression deficiency which was also observed in iPSC models. RUNX1 was identified as a key chr21 TF with siginificant transcriptional impact on regulation of multiple oncogenic pathways such as activation of PI3K/Akt/Wnt signaling in the RAD21 haploinsufficient DS-AMKL cells. This was correlated with activation of the Warburg effect/aerobic glycolysis which could be targeted pharmaceutically with the MK-2206 compound. This work shows that RAD21+/- in combination with GATA1s could be an indicator of highly glycolytic disease in DS-AMKL by upregulation of PI3K/Akt/Wnt through RUNX1 and that MK-2206 could be a candidate for targeted therapy for those patients.

Bio: Halla Rós started studying biology (BSc in Biology from University of Iceland, 2016) because she has always been interested in the many aspects of life and how it works. Functional genomics aiming to contribute to more targeted therapies for patients is at the top of her interest list. She has mainly worked in cancer research where she has studied the effect of specific mutations in blood cancers in correlation to the leukemic state, both in her PhD research (PhD in Medical Science from University of New South Wales, Sydney, 2025) as well as in her master’s (MSc in Medical Life Sciences from University of Iceland, 2018). During her PhD candidature she also supervised an honours student including all experimental planning and training of CRISPR/Cas9 gene editing work. During her MSc studies she became obsessed with learning how she could use the CRISPR/Cas9 system in her work so in 2017 she went to University of California, Berkeley for a CRISPR workshop hosted by Innovative Genomics Institute to learn from the Nobel Laureate Jennifer Doudna and other top experts in the world. This has been an important tool in her research ever since. After her MSc studies, before starting her PhD she worked at Landspítali, Department of Laboratory Hematology where she diagnosed blood disorders under the guidance of her MSc supervisor A/Prof Jón Þór Bergþórsson and guided a PhD exchange student. She also worked at Erna Magnúsdóttir Laboratory, BMC, University of Iceland as a CRISPR/Cas9 specialist for mouse embryonic stem cells. After many years in Sydney, Australia she has moved back home to Iceland and is excited to start her new job as a Senior Scientist in ARD Potency and Binding at Alvotech.