Zuzana Tothova, MD, PhD

Dana-Farber Cancer Institute

zuzana_tothova@dfci.harvard.edu

Dana-Farber Cancer Institute

zuzana_tothova@dfci.harvard.edu

Zuzana Tothova, MD, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

Assistant Professor, Medicine, Harvard Medical School
Investigator, Medical Oncology, Dana-Farber Cancer Institute
Associate Physician, Medicine, Brigham And Women's Hospital
Associate Member, Cancer Program, Broad Institute of MIT and Harvard

DF/HCC PROGRAM AFFILIATION

Cancer Genetics and Epigenetics, Member
Leukemia, Member

Research Abstract

The primary focus of the Tothova laboratory is investigation of the biology, genetics and treatment of myeloid malignancies, including the premalignant state of clonal hematopoiesis (CHIP), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Our goal is to contribute to our understanding of the effect of chromatin organization on hematopoietic stem cell (HSC) transformation in the context of mutations in cohesin genes and other epigenetic modulators recurrently mutated in myeloid malignancies. We employ a combination of genomic, genome engineering, mouse modeling as well as classical biochemistry, cellular and molecular biology approaches to answer disease-relevant questions with the goal to identify novel therapeutic targets that can be translated to true patient benefit in the future.

Jann JC, Tothova Z. Cohesin mutations in myeloid malignancies. Blood 2021. PubMed
Tothova Z, Valton AL, Gorelov RA, Vallurupalli M, Krill-Burger JM, Holmes A, Landers CC, Haydu JE, Malolepsza E, Hartigan C, Donahue M, Popova KD, Koochaki S, Venev SV, Rivera J, Chen E, Lage K, Schenone M, D'Andrea AD, Carr SA, Morgan EA, Dekker J, Ebert BL. Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML. JCI Insight 2021. PubMed
Cha HJ, Uyan Ö, Kai Y, Liu T, Zhu Q, Tothova Z, Botten GA, Xu J, Yuan GC, Dekker J, Orkin SH. Inner nuclear protein Matrin-3 coordinates cell differentiation by stabilizing chromatin architecture. Nat Commun 2021; 12:6241. PubMed
Lesch BJ, Tothova Z, Morgan EA, Liao Z, Bronson RT, Ebert BL, Page DC. Intergenerational epigenetic inheritance of cancer susceptibility in mammals. Elife 2019. PubMed
Tothova Z, Krill-Burger JM, Popova KD, Landers CC, Sievers QL, Yudovich D, Belizaire R, Aster JC, Morgan EA, Tsherniak A, Ebert BL. Multiplex CRISPR/Cas9-Based Genome Editing in Human Hematopoietic Stem Cells Models Clonal Hematopoiesis and Myeloid Neoplasia. Cell Stem Cell 2017; 21:547-555.e8. PubMed
Tothova Z, Ebert BL. Doubling Down on Mutant RAS Can MEK or Break Leukemia. Cell 2017; 168:749-750. PubMed
Puram RV, Kowalczyk MS, de Boer CG, Schneider RK, Miller PG, McConkey M, Tothova Z, Tejero H, Heckl D, Järås M, Chen MC, Li H, Tamayo A, Cowley GS, Rozenblatt-Rosen O, Al-Shahrour F, Regev A, Ebert BL. Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML. Cell 2016; 165:303-16. PubMed
Elf S, Abdelfattah NS, Chen E, Perales-Paton J, Rosen EA, Ko A, Peisker F, Florescu N, Giannini S, Wolach O, Morgan EA, Tothova Z, Losman JA, Schneider RK, Al-Shahrour F, Mullally A. Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation. 2016. PubMed
Doench JG, Fusi N, Sullender M, Hegde M, Vaimberg EW, Donovan KF, Smith I, Tothova Z, Wilen C, Orchard R, Virgin HW, Listgarten J, Root DE. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat Biotechnol 2016; 34:184-191. PubMed
Doench JG, Hartenian E, Graham DB, Tothova Z, Hegde M, Smith I, Sullender M, Ebert BL, Xavier RJ, Root DE. Rational design of highly active sgRNAs for CRISPR-Cas9-mediated gene inactivation. Nat Biotechnol 2014. PubMed
Tothova Z, Berliner N. Hemophagocytic Syndrome and Critical Illness: New Insights into Diagnosis and Management. J Intensive Care Med 2014. PubMed

Hartwell KA, Miller PG, Mukherjee S, Kahn AR, Stewart AL, Logan DJ, Negri JM, Duvet M, Järås M, Puram R, Dancik V, Al-Shahrour F, Kindler T, Tothova Z, Chattopadhyay S, Hasaka T, Narayan R, Dai M, Huang C, Shterental S, Chu LP, Haydu JE, Shieh JH, Steensma DP, Munoz B, Bittker JA, Shamji AF, Clemons PA, Tolliday NJ, Carpenter AE, Gilliland DG, Stern AM, Moore MA, Scadden DT, Schreiber SL, Ebert BL, Golub TR. Niche-based screening identifies small-molecule inhibitors of leukemia stem cells. Nat Chem Biol 2013; 9:840-8. PubMed
Tothova Z, Steensma DP, Ebert BL. New strategies in myelodysplastic syndromes: application of molecular diagnostics to clinical practice. Clin Cancer Res 2013; 19:1637-43. PubMed
Tothova Z, Wagner AJ. Anaplastic lymphoma kinase-directed therapy in inflammatory myofibroblastic tumors. Curr Opin Oncol 2012; 24:409-13. PubMed
Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, Ferraro F, Mercier F, Singh H, Brumme KM, Acharya SS, Scholl C, Schöll C, Tothova Z, Attar EC, Fröhling S, DePinho RA, Armstrong SA, Gilliland DG, Scadden DT. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell 2011; 146:697-708. PubMed
Cornejo MG, Mabialah V, Sykes SM, Khandan T, Lo Celso C, Lopez CK, Rivera-Muñoz P, Rameau P, Tothova Z, Aster JC, DePinho RA, Scadden DT, Gilliland DG, Mercher T. Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification. Blood 2011; 118:1264-73. PubMed
Lee JY, Nakada D, Yilmaz OH, Tothova Z, Joseph NM, Lim MS, Gilliland DG, Morrison SJ. mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion. Cell Stem Cell 2010; 7:593-605. PubMed
Tothova Z, Gilliland DG. A radical bailout strategy for cancer stem cells. Cell Stem Cell 2009; 4:196-7. PubMed
Lee BH, Tothova Z, Levine RL, Anderson K, Buza-Vidas N, Cullen DE, McDowell EP, Adelsperger J, Fröhling S, Huntly BJ, Beran M, Jacobsen SE, Gilliland DG. FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell 2007; 12:367-80. PubMed
Tothova Z, Gilliland DG. FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell 2007; 1:140-52. PubMed
Tothova Z, Mercher T. [FoxO: stress or eternal life]. Med Sci (Paris) 2007; 23:466-7. PubMed
Klose RJ, Yan Q, Tothova Z, Yamane K, Erdjument-Bromage H, Tempst P, Gilliland DG, Zhang Y, Kaelin WG. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 2007; 128:889-900. PubMed
Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C, Armstrong SA, Passegué E, DePinho RA, Gilliland DG. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007; 128:325-39. PubMed
Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho RA. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 2007; 128:309-23. PubMed
Masutomi K, Possemato R, Wong JM, Currier JL, Tothova Z, Manola JB, Ganesan S, Lansdorp PM, Collins K, Hahn WC. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proc Natl Acad Sci U S A 2005; 102:8222-7. PubMed
Gu TL, Tothova Z, Scheijen B, Griffin JD, Gilliland DG, Sternberg DW. The NPM-ALK Fusion Kinase of Anaplastic Large Cell Lymphoma Regulates Survival and Proliferative Signaling Through Modulation of FOXO3a. Blood 2004; 103:4622-9. PubMed

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Zuzana Tothova, MD, PhD

Dana-Farber Cancer Institute

Similar Members

Similar Members

Zuzana Tothova, MD, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

DF/HCC PROGRAM AFFILIATION

Research Abstract

Publications from Harvard Catalyst Profiles

Similar Members

Similar Members