Page 46 - Hormel Institute Annual Report 2021-22
P. 46

 Current research projects:
1) Studies on the role of the HIF1A-DNMT3A axis in AML1/ETO-driven acute myeloid leukemia
2) Studies on the role of RNA m6A aberrations in
protein kinase-targeted cancer therapy
3) Studies on the use of RNA nanotechnology to
deliver siRNAs/small molecule inhibitors to overcome resistance to molecular-targeted therapies
 Shujun Liu, PhD
 “Our discoveries offer new insights into the molecular biology of cancer pathogenesis
and drug resistance, identify new prognostic biomarkers and therapeutic targets, and develop novel therapeutic reagents to improve
the management of cancerous lesions.”
Shujun Liu
46 | THE HORMEL INSTITUTE // Cancer Epigenetics and
Experimental Therapeutics
ASSISTANT DIRECTOR FOR RESEARCH / PROFESSOR
UNIVERSITY OF MINNESOTA
  Our research aims at understanding the causes and the impacts of aberrant epigenetics, protein kinases, and RNA/DNA
N6-Methyladenosine (m6A) in cancer pathogen- esis and resistance to therapeutics, including chemotherapies and molecular targeted therapies. To approach our goals, we use a multidisciplinary approach with molecular biology, in vivo modeling and human biospecimens as our cornerstones
to identify and validate inhibitory molecules to restore key antineoplastic features of kinase signaling, epigenetic landscapes and m6A methylation in human cancer cells. Specifically, we have the following innovative projects:
Studies on the role of the HIF1A-DNMT3A axis in AML1/ETO-driven acute myeloid leukemia
Hypoxia-inducible factor 1a (HIF1a) is a key transcription factor in cancers and a well-studied oncogene. However, most previous studies focused on non-leukemic malignancies, and HIF1a was presumed to be mainly hypoxia-dependent factor in cancers. Limited, but accumulating
evidence suggests that hypoxia- independent mechanisms for HIF signaling is another hallmark for cancers. Indeed, HIF signaling
has been found to be activated by factors involved in hematopoiesis, such as MEIS1, TPO, and SCF, as well as gene mutations (i.e., FLT3- ITD) in leukemia. In relation to this project, we showed that HIF1a is transcriptionally activated by AML1/ ETO (AE) and significantly promotes
AE+ leukemia growth. However, it warrants further investigation of the details of the molecular mechanisms involved and the biological and therapeutic outcomes of this hypoxia-independent HIF1a activation. Given that AE-upregulated HIF1a transactivates DNMT3a followed by DNA hypermethylation, DNA methylation changes may represent one endpoint of hypoxia-independent HIF1a activation. Functionally, we showed that within AE+ subgroup, the patients with high HIF1a and DNMT3a expression survive much shorter than those with low expression. Thus, we are proposing to test the hypothesis that HIF1a may promote AE leukemogenicity through enhancing AE transcriptional activities and modulating AE-governed DNA methylation landscape in
AML cells; and that the gain-of-function of
the AE-HIF1a-DNMT3a axis may be a reliable molecular marker and vulnerable target, which defines patients with a poor prognosis in an otherwise prognostically favorable AE+ subgroup AML (Figure 1). Findings will advance our understanding of AE+ AML molecular pathology as well as the aberrant epigenetics and the oncogenic functions of hypoxia-independent HIF1a signaling in cancers, including solid tumors. Findings will also lay the groundwork to develop newer strategies to better target AE+ AML.
     









































































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