Olga Guryanova

Olga Guryanova, MD, Ph.D.

AST PROF

Department: MD-PHARMACOLOGY / THERAPEUTICS
Business Phone: (352) 294-8590
Business Email: oguryanova@ufl.edu

Research Profile

The overarching research goal of the Guryanova Lab is to delineate the mechanisms of the cross-talk between epigenetics and chromatin organization, learning how these processes apply to the development of acute myeloid leukemia (AML), resistance to therapies, and clonal evolution. Ultimately, Dr. Guryanova would like to harness this mechanistic understanding to develop improved therapeutic approaches for leukemia.

DNA methyltransferase 3A (DNMT3A) is the third most commonly mutated gene in AML, present in up to 30% of all de novo AML cases. Clinical observations show that together, with alterations in NPM1 and by activating internal tandem duplication in FLT3, mutations in DNMT3A define a subtype of AML — one with a particularly grave prognosis due to high disease relapse rates. The majority of DNMT3A mutations result in a single amino acid substitution at arginine 882 (R882), leading to decreased processivity of the DNA methylation, although the enzymatic activity, per se, is retained. DNMT3A mutations are among the earliest genetic events in leukemogenesis present in pre-leukemic hematopoietic stem cells (HSCs). The frequent finding of DNMT3A(R882) in elderly individuals with clonal hematopoiesis but without hematologic malignancies suggests that these mutations may drive clonal evolution towards increased HSC fitness and competitive advantage.

The lab has developed a clinically-accurate genetic mouse model of Dnmt3a-mutant AML. Using this model, they have shown that presence of mutant Dnmt3a renders the cells less sensitive to daunorubicin, a standard anti-leukemic chemotherapeutic agent of the anthracycline family. This chemoresistance is specific to anthracycline-induced DNA intercalation and torsional stress, and it is independent of topoisomerase 2 inhibition. These findings align well with clinical observations that mutant DNMT3A defines chemoresistant leukemic and that pre-leukemic clones that survive induction chemotherapy persist in remission and give rise to disease relapse. Subsequent biochemical studies identified a defect in nucleosome eviction and chromatin remodeling through attenuated recruitment of histone chaperones as a molecular mechanism of increased DNA torsional stress tolerance.

The current work in the lab is focused on further delineation of the molecular mechanisms underlying altered chromatin remodeling, on the investigation of clonal evolution in the blood system, and on the pre-clinical evaluation of candidate therapeutic approaches for DNMT3A-mutant leukemia.

Publications

2021
HOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia.
Nature communications. 12(1) [DOI] 10.1038/s41467-021-22095-2. [PMID] 33782403.
2020
Alterations to DNMT3A in Hematologic Malignancies.
Cancer research. [DOI] 10.1158/0008-5472.CAN-20-3033. [PMID] 33087320.
2020
DNMT3A alterations associated with myeloid malignancies dictate differential responses to hypomethylating agents.
Leukemia research. 94 [DOI] 10.1016/j.leukres.2020.106372. [PMID] 32445940.
2019
Catalytically inactive Dnmt3b rescues mouse embryonic development by accessory and repressive functions.
Nature communications. 10(1) [DOI] 10.1038/s41467-019-12355-7. [PMID] 31558711.
2019
Disulfide bond-disrupting agents activate the tumor necrosis family-related apoptosis-inducing ligand/death receptor 5 pathway.
Cell death discovery. 5 [DOI] 10.1038/s41420-019-0228-9. [PMID] 31839995.
2018
Loss of Dnmt3a Immortalizes Hematopoietic Stem Cells In Vivo.
Cell reports. 23(1):1-10 [DOI] 10.1016/j.celrep.2018.03.025. [PMID] 29617651.
2017
FQI1: a transcription-methylation switch for cancer.
Oncotarget. 8(8):12536-12537 [DOI] 10.18632/oncotarget.15087. [PMID] 28177910.
2016
Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model.
Molecular cancer research : MCR. 14(2):185-95 [DOI] 10.1158/1541-7786.MCR-15-0281. [PMID] 26538284.
2016
DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling.
Nature medicine. 22(12):1488-1495 [DOI] 10.1038/nm.4210. [PMID] 27841873.
2016
Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells.
Leukemia. 30(5):1133-42 [DOI] 10.1038/leu.2015.358. [PMID] 26710888.
2015
CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.
Cancer cell. 28(1):15-28 [DOI] 10.1016/j.ccell.2015.06.006. [PMID] 26175413.
2014
A WIMSical approach to decoding DNA methylation in myeloid leukemia.
Genome biology. 15(9) [PMID] 25315876.
View on: PubMed
2013
Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo.
The Journal of experimental medicine. 210(12):2641-59 [DOI] 10.1084/jem.20131141. [PMID] 24218140.
2013
Facilitates chromatin transcription complex is an “accelerator” of tumor transformation and potential marker and target of aggressive cancers.
Cell reports. 4(1):159-73 [DOI] 10.1016/j.celrep.2013.06.013. [PMID] 23831030.
2012
DNMT3A and stem cell function: new insights into old pathways.
Haematologica. 97(3) [DOI] 10.3324/haematol.2012.064410. [PMID] 22383741.
2012
IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype.
Nature. 483(7390):479-83 [DOI] 10.1038/nature10866. [PMID] 22343889.
2012
Platelet-derived growth factor receptors differentially inform intertumoral and intratumoral heterogeneity.
Genes & development. 26(11):1247-62 [DOI] 10.1101/gad.193565.112. [PMID] 22661233.
2011
Curaxins: anticancer compounds that simultaneously suppress NF-κB and activate p53 by targeting FACT.
Science translational medicine. 3(95) [DOI] 10.1126/scitranslmed.3002530. [PMID] 21832239.
2011
Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells.
Nature cell biology. 13(2):142-52 [DOI] 10.1038/ncb2153. [PMID] 21258371.
2011
L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1.
The EMBO journal. 30(5):800-13 [DOI] 10.1038/emboj.2011.10. [PMID] 21297581.
2011
Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3.
Cancer cell. 19(4):498-511 [DOI] 10.1016/j.ccr.2011.03.004. [PMID] 21481791.
2010
Cancer stem cells in glioblastoma–molecular signaling and therapeutic targeting.
Protein & cell. 1(7):638-55 [DOI] 10.1007/s13238-010-0078-y. [PMID] 21203936.

Grants

Sep 2021 ACTIVE
DNMT3A loss facilitates KMT2C-induced enhancer switching in myeloid malignancies
Role: Co-Investigator
Funding: EVANS MEDICAL FOU
Jul 2020 ACTIVE
Novel combinatorial treatment approaches to augment sensitivity to cytarabine in acute myeloid leukemia with DNMT3A mutations
Role: Principal Investigator
Funding: OCALA ROYAL DAMES FOR CANCER RESEARCH
Apr 2020 ACTIVE
Bad Blood: How Mutations in the Blood System Contribute to Aggressive Phenotype of Solid Tumors
Role: Principal Investigator
Funding: UF FOU
Jul 2019 ACTIVE
The role of DNMT3A mutations in clonal heterogeneity and evolution of hematopoiesis
Role: Principal Investigator
Funding: NATL INST OF HLTH NIDDK
Apr 2018 ACTIVE
Ionizing radiation induced hematological malignancies
Role: Project Manager
Funding: NATL INST OF HLTH NCI
Nov 2017 ACTIVE
The Harry T. Mangurian, Jr. Foundation – Support for the Study of Therapy Resistant Leukemia
Role: Co-Investigator
Funding: UF FOU via HARRY T MANGURIAN JR FOU
Sep 2016 – Aug 2020
Biologic and therapeutic relevance of DNMT3A mutations in acute myeloid leukemia
Role: Principal Investigator
Funding: NATL INST OF HLTH NCI
Feb 2015 ACTIVE
UF Health Cancer Center Pilot Project Grants funded through the Florida Consortium of National Cancer Institute Centers Program
Role: Project Manager
Funding: UF HEALTH SHANDS HOSPITAL

Teaching Profile

Courses Taught
2018-2021
GMS6560 Molecules to Man: Past, Present and Future Therapeutic Strategies for Disease
2020-2021
GMS6001 Fundamentals of Biomedical Sciences I
2019-2021
GMS6530 Medical Pharmacology and Therapeutics II: Cardiovascular, Renal and Respiratory Systems
2019-2021
GMS6540 GMS 6840 Medical Pharmacology and Therapeutics IV: Cancer, Antimicrobial and Antiparasitic Agents
2020-2021
PAS5026 Pharmacotherapeu 2
2020-2021
BMS6816 Cancer Bio Clin Oncol
2018-2021
DEN6262 Prin of Pharmacology
2018,2020-2021
GMS6009 Principles of Drug Action and Therapeutics
2018
GMS7980 Research for Doctoral Dissertation
2018
GMS7979 Advanced Research
2021
GMS6421 Cell Biology
2021
GMS6504 Advanced Medical Pharmacology
2021
GMS6065 Fundamentals of Cancer Biology
2021
GMS6053 Cancer Biology and Therapeutics

Contact Details

Phones:
Business:
(352) 294-8590
Emails:
Business:
oguryanova@ufl.edu