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2885 RNF5 Defines Acute Myeloid Leukemia Growth and Susceptibility to Histone Deacetylase Inhibitors

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster III
Hematology Disease Topics & Pathways:
Biological, AML, apoptosis, Diseases, Biological Processes, epigenetics, Myeloid Malignancies, Clinically relevant
Monday, December 7, 2020, 7:00 AM-3:30 PM

Ali Khateb, PhD1,2*, Anagha Deshpande, PhD1*, Yongmei Feng, PhD1*, Ikrame Lazar, PhD1,2*, Joo Sang Lee, PhD3*, Bertrand Fabre, PhD1,2*, Yan Li, PhD1*, Darren Finlay4*, Yu Fujita, PhD1,5*, Tongwu Zhang, PhD6*, Ian Pass, PhD1*, Ido Livneh, PhD2*, Carol Burian7*, James R. Mason, MD7*, Ronit Almog, MD8*, Nurit Horesh, MD9*, Yishai Ofran, MD2,9, Kevin Brown6*, Kristiina Vuori, PhD1*, Michael Jackson, PhD1*, Eytan Ruppin, PhD3*, Aniruddha J. Deshpande, PhD1 and Ze'ev A. Ronai, PhD1,2*

1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
2Technion Integrated Cancer Center, Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel
3Cancer Data Science Lab, National Cancer Institute, National Institute of Health, Bethesda, MD
4Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
5Division of Respiratory Medicine, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
6Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
7Scripps MD Anderson Cancer Center, La Jolla, CA
8Rambam Health Care Campus, Epidemiology Department and Biobank, Haifa, Israel
9Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel

Acute myeloid leukemia (AML) remains an incurable blood cancer largely due to rapid emergence of resistance to conventional treatments. Thus, new therapeutic modalities are greatly needed to halt AML development. Here, using genetic and xenograft mouse models, we reveal that inhibition of the ubiquitin ligase RNF5 in human AML cell lines and in MLL-AF9-driven AML severely decreased the leukemogenic potential of those cells and prolonged survival of model leukemic mice. These findings suggest the possibility that targeting a single gene, namely RNF5, could effectively inhibit different AML subtypes. We initially focused on RNF5 as its expression is upregulated in AML patient cohorts as well as in AML-derived cell lines compared with normal hematopoietic cells. Furthermore, high RNF5 expression in AML patient specimens correlated with poor prognosis, relapse and short overall patient survival. By contrast, specimens from AML patients who responded to therapy exhibited low RNF5 levels. In vitro, RNF5 loss impaired the clonogenic potential of MLL-AF9-transduced bone marrow cells and markedly attenuated growth and survival of AML but not CML or T-ALL cell lines, in which RNF5 is also highly expressed. High-throughput screen and bioinformatics analysis identified RNF5 and ER-associated degradation (ERAD) components, as augmenting AML cell sensitivity to histone deacetylase (HDAC) inhibition. Indeed, inhibition of RNF5 sensitized AML cells to HDAC inhibitors. Correspondingly, a favorable prognosis was observed in AML patients exhibiting low expression of RNF5 and HDAC. Collectivity, our studies identify a potential new therapeutic modality based on targeting RNF5 to inhibit AML and suggest that RNF5 expression could serve as a prognostic marker and means to stratify patients for treatment with HDAC inhibitors.

Disclosures: Ofran: AbbVie: Membership on an entity's Board of Directors or advisory committees. Vuori: Bionano Genomics: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH