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Perna Lab

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The Surfaceome of Hematologic Malignancies for Immune Targeting

Immunotherapy is an emerging treatment for cancer based on the success of antibody-mediated checkpoint blockade and engineered T cells. While impressive progress has been made in tumor immunology and clinical application of immunomodulatory agents in solid tumors, we don’t fully understand how to effectively incorporate immunotherapeutic strategies in hematologic malignancies. We previously developed a target discovery strategy to identify Chimeric Antigen Receptor (CAR) targets in Acute Myeloid Leukemia (Perna F et al., Cancer Cell 2017). We investigate how essential genetic and epigenetic determinants of AML shape the leukemia cell surfaceome, thus providing targets for promoting leukemogenesis and use of precision immunotherapy. We mine composite high-throughput proteomic and transcriptomic data from human and mouse genetic models and utilize primary patient samples in search of novel immunotherapeutic targets. The lab has an expertise in virally expressing genetic mutations in primary hematopoietic stem and progenitor cells and performing large scale multi-omic studies, including cell surface-specific proteomics followed by Mass-Spectrometry analysis and single-cell RNA-seq analysis. We generate multiple xenografts including PDX models that we use to assess the efficacy of novel CAR T-cells. Our accurate proteogenomic approach for target discovery also includes computational work as we develop our own integrated datasets for cell surface molecule annotation and inform CAR design. We investigate the role of the cancer cell surfaceome in immune-mediated mechanisms contributing to cancer’s immune evasion and dependent on disease genetics. Join our lab!
44428-Perna, Fabiana

Fabiana Perna, MD, PhD

Associate Professor of Medicine

Fabiana Perna a physician-scientist focused on the pathogenesis and treatment of hematological malignancies. She holds a full-time faculty position in tenure-track as an independent investigator in the Department of Medicine, Division of Hematology/Oncology at Indiana University School of Medicine.

Dr. Perna completed clinical training as hematologist under the mentorship of Dr. Bruno Rotoli, leading hematologist in Italy. In 2008, she joined the laboratory of Dr. Stephen Nimer at Memorial Sloan Kettering Cancer Center, where she acquired scientific skills to model myeloid malignancies with cord blood CD34+ cells. During that time, she contributed investigating the role of several recurring epigenetic mutations in normal and malignant hematopoiesis, while completing a PhD program. These studies were published on several high-impact scientific journals (Cancer Cell, Science, Blood, Cell Stem Cells, Nature Biotech, PNAS etc) and she was awarded an American Italian Cancer Foundation fellowship, the clinical fellowship of Memorial Sloan Kettering Cancer Center, the Translational Research Training in Hematology (TRTH) and a competitive American Society of Hematology (ASH) Scholar Award in the clinical/translational category.

At the end of 2012, she joined the laboratory of Dr. Michel Sadelain, one of the pioneers of Chimeric Antigen Receptor (CAR) T-cell therapy targeting CD19 antigen in lymphoid malignancies, where she worked as a senior research scientist. Given the exciting times in cancer immunotherapy and her previous expertise in myeloid malignancies, she developed a compelling platform, which integrates proteomics and transcriptomics to unbiasedly identify CAR T cells targets for Acute Myeloid Leukemia (Perna F et al., Cancer Cell 2017). From 2016 to 2018 she was the PI on a Technology Development Fund from MSKCC of $500K.

In June 2019, Dr. Perna joined Indiana University School of Medicine as an independent investigator with her own lab space and large start-up funds. Here, she was awarded one grant from the Leukemia Research Foundation, two internal grants from IU School of Medicine and one large award from a pharma to develop novel CAR T-cell therapy. Given her expertise, she has recently discussed CAR T-cell target selection (Perna F. Molecular Therapy 2021) and is an active member of the ASH Immunotherapy Committee. She holds a joint faculty appointment in the Department of Biochemistry and Molecular Biology, and is co-inventor of multiple patents that have been licensed. She also takes care of patients with hematologic malignancies in the Bone Marrow Transplantation (BMT) unit of the IU Health University Hospital and IU Bren and Simon NCI-Comprehensive Cancer Center.

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Publications

Dong, C., Cesarano, A., Bombaci, G. et al. Intron retention-induced neoantigen load correlates with unfavorable prognosis in multiple myeloma. Oncogene 2021 Sep 9.

Perna F. Safety starts with selecting the targets. Mol Ther 2021 Feb 3;29(2):424-425

Haubner S, Perna F, Kohnke T, Schmidt C, Berman S, Augsberger C, Schnorfeil FM, Krupka C, Lichtenegger S, Liu X, Kerbs P, Schneider S, Metzeler KH, Spiekermann K, Hiddemann W, Greif PA, Herold T, Sadelain M, Subklewe M. Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML. Leukemia 2018 Jun 26.

Perna F, Berman S, Soni R, Mansilla-Soto J, Eyquem J, Hamieh M, Hendrickson R, Brennan C, Sadelain M. Integrating proteomics and transcriptomics for systematic combinatorial chimeric antigen receptor therapy of AML. Cancer Cell 2017 Oct 9;32(4):506-519.e5.

Perna F and Sadelain M. Myeloid leukemia switch as immune escape from CD19 CAR therapy. Translational Cancer Research 2017 August 5(S2):S221-S225

Ghosh A, Smith M, James SE, Davila ML, Velardi E, Argyropoulos KV, Gunset G, Perna F, Kreines FM, Levy ER, Lieberman S, Jay HV, Tuckett AZ, Zakrzewski JL, Tan L, Young LF, Takvorian K, Dudakov JA, Jenq RR, Hanash AM, Motta AC, Murphy GF, Liu C, Schietinger A, Sadelain M, van den Brink MR. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nature Medicine 2017 Feb;23(2):242-249.

Liu F, Wang L, Perna F, Nimer S. Beyond transcription factors: how oncogenic signaling pathways re-shape the epigenetic landscape. Nature Cancer Reviews 2016 Jun;16(6):359-72.

Perna F*, Vu LP, Themeli M, Kriks S, Hoya-Arias R, Khanin R, Hricik T, Mansilla-Soto J, Papapetrou EP, Levine RL, Studer L, Sadelain M, Nimer SD. The Polycomb Group Protein L3MBTL1 Represses a SMAD5-Mediated Hematopoietic Transcriptional Program in Human Pluripotent Stem Cells. Stem Cell Reports 2015 Apr 14;4(4):658-69. *corresponding author

  • Additional Publications

    Boulad F, Shore T, van Besien K, Minniti C, Barbu-Stevanovic M, Wiener Fedus S, Perna F, Greenberg J, Guarneri D, Nandi V, Mauguen A, Yazdanbakhsh K, Sadelain M, Shi P. Safety and efficacy of plerixafor dose escalation for the mobilization of CD34+ hematopoietic progenitor cells in patients with sickle cell disease: interim results. Haematologica 2018 Feb 1.

    Sansone P, Berishaj M, Rajasekhar VK, Ceccarelli C, Chang Q, Strillacci A, Savini C, Shapiro L, Bowman RL, Mastroleo C, De Carolis S, Daly L, Benito-Martin A, Perna F, Fabbri N, Healey JH, Spisni E, Cricca M, Lyden D, Bonafé M, Bromberg J. Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles. Cancer Research 2017 Apr 15;77(8):1927-1941.

    Sansone P, Ceccarelli C, Berishaj M, Chang Q, Rajasekhar V, Perna F, Bowman R, Vidone M, Daly L, Nnoli J, Santini D, Taffurelli M, Shih N, Feldman M, Mao J, Colameco C, Chen J, DeMichele A, Fabbri N, Healey J, Cricca M, Gasparre G, Lyden D, Bonafé M Bromberg J. Self renewal of CD133hi cells by IL6/Notch3 signaling regulates endocrine resistance in metastatic breast cancers. Nature Communications 2016 Feb 9;7:10442.

    Zhao Z, Condomines M, van der Stegen S, Perna F, Kloss C, Gunset G, Plotkin J, Sadelain M. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 2015 Oct 12;28(4):415-28.

    Liu F, Cheng G, Hamard PJ, Greenblatt S, Wang L, Man N, Perna F, Xu H, Tadi M, Luciani L, Nimer SD. Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis. Journal of Clinical Investigation 2015 Sep 1;125(9):3532-44

    Kotini AG, Chang CJ, Boussaad I, Delrow JJ, Dolezal EK, Nagulapally AB, Perna F, Fishbein GA, Klimek VM, Hawkins RD, Huangfu D, Murry CE, Graubert T, Nimer SD, Papapetrou EP. Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells. Nature Biotechnology 2015 Jun;33(6):646-55.

    Masarone M, De Renzo A, La Mura V, Sasso FC, Romano M, Signoriello G, Rosato V, Perna F, Pane F, Persico M. Management of the HBV reactivation in isolated HBcAb positive patients affected with Non Hodgkin Lymphoma. BMC Gastroenterol 2014 Feb 17;14(1):31.

    Vu L, Perna F, Wang L, Voza F, Figueroa ME, Tempst P, Erdjument-Bromage H, Gao R, Chen S, Paietta E, Deblasio T, Melnick A, Liu Y, Zhao X and Nimer SD. PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex. Cell Reports 2013 Dec 26;5(6):1625-38.

    Themeli M, Kloss CC, Ciriello G, Fedorov VD, Perna F, Gonen M and Sadelain M. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nature Biotechnology 2013 Oct;31(10):928-33.

    Bazzoli E, Pulvirenti T, Oberstadt M, Perna F, Wee B, Schultz N, Huse JT, Fomchenko EI, Voza F, Tabar V, Brennan CW, DeAngelis LM, Nimer SD, Holland EC, Squatrito M. MEF promotes stemness in the pathogenesis of gliomas. Cell Stem Cell 2012 Dec 7;11(6):836-844.

    Abdel-Wahab O, Adli M, Lafave LM, Gao J, Hricik T, Shih AH, Pandey S, Patel JP, Chung YR, Koche R, Perna F, Zhao X, Taylor JE, Park CY, Carroll M, Melnick A, Nimer SD, Jaffe JD, Aifantis I, Bernstein BE, Levine RL. ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression. Cancer Cell 2012 Aug 14;22(2):180-93.

    Wang L, Gural A, Sun X, Zhao X, Perna F, Huang G, Hatlen MA, Vu L, Liu F, Xu H, Asai T, Xu H, Deblasio T, Menendez S, Voza F, Jiang Y, Cole PA, Zhang J, Melnick A, Roeder RG, Nimer SD. The leukemogenicity of AML1- ETO is dependent on site-specific lysine acetylation. Science 2011 Aug 5;333(6043):765-9.

    Perna F, Abdel-Wahab O, Levine RL, Jhanwar SC, Imada K, Nimer SD. ETV6-ABL1-positive "chronic myeloid leukemia": clinical and molecular response to tyrosine kinase inhibition. Haematologica 2011 Feb;96(2):342-3.

    Liu F, Zhao X, Perna F, Wang L, Koppikar P, Abdel-Wahab O, Harr MW, Levine RL, Xu H, Tefferi A, Deblasio A, Hatlen M, Menendez S, Nimer SD. JAK2V617F-Mediated Phosphorylation of PRMT5 Downregulates Its Methyltransferase Activity and Promotes Myeloproliferation. Cancer Cell 2011 Feb 15;19(2):283-94.

    Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, Figueroa M, Vasanthakumar A, Patel J, Zhao X, Perna F, Pandey S, Madzo J, Song C, Dai Q, He C, Ibrahim S, Beran M, Zavadil J, Nimer SD, Melnick A, Godley LA, Aifantis I, Levine RL. TET2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 2011 Jul 12;20(1):11-2.

    Moulik K, Ahn J, Zong H, Rodina A, Cerchietti L, DaGAma E, Cladas-Lopes E, Beebe K, Perna F, Hatzi K, Vu LP, Zhao X, Zatorska D, Taldone T, Smith-Jones P, Alpaugh M, Gross SS, Pillarsetty N, Ku T, Lewis JS, Larson SM, Levine R, Erdjument-Bromage H, Guzman ML, Nimer SD, Melnick A, Neckers L, Chiosis G. A small molecule Hsp90 inhibitor provides a global overview of proteome alterations in cancer. Nature Chemical Biology 2011 Sep 25;7(11):818-26.

    Hoya-Arias R, Tomishima M, Perna F, Voza F, Nimer SD. L3MBTL1 deficiency directs the differentiation of human embryonic stem cells towards trophectoderm. Stem Cells Development 2011 Nov;20(11):1889-900.

    Risitano A and Perna F. Aplastic Anemia: Immunosuppressive therapy in 2010. Pediatric Reports 2011 Jun 22;3 26. Perna F, Gurvich N, Hoya-Arias R, Abdel-Wahab O, Levine RL, Asai T, Voza F, Menendez S, Wang L, Liu F, Zhao X, Nimer SD. Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q- polycythemia vera. Blood 2010 Oct 14;116(15):2812-21.

    Gurvich N, Perna F, Farina A, Voza F, Menendez S, Hurwitz J, Nimer S. L3MBTL1 polycomb protein, a candidate tumor suppressor in del(20q12) myeloid disorders, is essential for genome stability. Proceedings National Academy Science U S A. 2010 Dec 28;107(52)

    Battipaglia G, Avilia S, Morelli E, Caranci F, Perna F, Camera A. Posterior reversible encephalopathy syndrome (PRES) during induction chemotherapy for acute myelobalstic leukemia (AML). Annals Hematology 2012 Aug;91(8):1327-8.

    Risitano AM, Perna F and Selleri C. Achievements and Limitations of Complement Inhibition by Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: The Role of Complement Component 3. Mini Review Medical Chemistry 2011 Jun 1;11(6):528-35.

    Strianese D, Tranfa F, Finelli M, De Renzo A, Stabaino S, Schiemer R, Cardone D, Pacelli R, Perna F, Mascolo M, De Rosa G, Bonavolontà G. Hepatitis C Virus Infection in Ocular Adnexal Lymphomas. Arch Ophthalmology 2010 Oct;128(10):1295-9.

    Storto G, De Renzo A, Pellegrino T, Perna F, De Falco T, Erra P, Nardelli A, Speranza A, Klain M, Rotoli B, Pace L. Assessment of Metabolic Response to Radioimmunotherapy with 90Y-Ibritumomab Tiuxetan in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma. Radiology 2010 Jan; 254(1):245-52.

    De Renzo A, Perna F, Persico M, Notaro R, Mainolfi C, de Sio I, Ciancia G, Picardi M, Del Vecchio L, Pane F, Rotoli B. Excellent prognosis and HCV infection prevalence in Primary Hepatic and Splenic Lymphoma. European Journal of Hematology 2008 Jul;81(1):51-7.

    La Mura V, De Renzo A, Perna F, D'Agostino D, Masarone M, Romano M, Bruno S, Torella R, Persico M. Antiviral therapy after complete response to chemotherapy could be efficacious in HCV-positive non-Hodgkin’s lymphoma. J Hepatology 2008 Oct;49(4):557-63.

    De Renzo A, Perna F, Mainolfi C, Pace L, Rotoli B. 18F-FDG/CT avid sites mimicking lymphoma. BloodMed 2007.

    De Renzo A, Perna F, Persico M, Mainolfi C, Pace L. 18F-fluorodeoxyglucose positron emission tomography/computed tomography in the evaluation of early response in a primary hepatic lymphoma. British Journal of Haematology 2006 Jun;133(6):580

    De Renzo A, Perna F, Romano M, Rotoli B. Multiple lymphomatous polyposis of the entire GI tract: report of two case. Haema 2006 vol 9; n 2; pg 282-285.

Research

Photomicrograph of bone marrow aspirate showing myeloblasts of acute myeloid leukemia (AML), a cancer of white blood cells.

Acute Myeloid Leukemia

Advances in genomic and epigenomic characterization of acute myeloid leukemia (AML) have fostered better understanding of leukemogenesis, paving the way for development and approval of several novel targeted therapies. Despite that, the clinical outcome of AML patients remains dismal, with a 5-year overall survival of approximately 27%, prompting the search for additional and synergistic therapeutic rationales. Immunotherapy is an emerging treatment for cancer based on the success of antibody-mediated checkpoint blockade and engineered T cells. Historically, AML has been considered an immuno-responsive malignancy and continues to represent the most common indication for which patients receive allogeneic stem cell transplantation (alloHSCT). However, developing immune-based therapies for AML has been challenged by the lack of suitable surface targets, complex clonal heterogeneity and increased recognition of immunosuppressive factors within the bone marrow (BM) microenvironment. Based on extensive experience in myeloid malignancies and target discovery strategies for Chimeric Antigen Receptor (CAR) T-cell targets, we investigate how driver AML mutations may alter the leukemia-specific surface proteome, thus providing targets promoting leukemogenesis and for use of immunotherapy. It is our goal to identify biologically and therapeutically relevant leukemia surface targets than can most effectively harness the promise of anti-AML immunotherapy. To undertake this challenge, we use an accurate method involving integration of computational and experimental approaches based on proteomic and transcriptome data of genetic models.

Bone marrow aspirate cytology of multiple myeloma, a type of bone marrow cancer of malignant plasma cells, associated with bone pain, bone fractures and anemia.

Multiple Myeloma

Multiple myeloma (MM) is an incurable malignancy of mature plasma cells. It accounts for 1.8% of all new cancer cases annually. Despite major advances in the therapeutic armamentarium of MM, only 50.7% survive more than 5 years after diagnosis, with significantly lower rates (21% at 5 years) for high-risk patients. Targeting tumor antigens with immunotherapy is rapidly emerging as a promising approach for MM treatment. Monoclonal antibodies, antibody-drug conjugates, bi-specific antibody constructs, and Chimeric Antigen Receptor (CAR) T-cell therapy targeting BCMA (B-cell maturation antigen) are significantly improving survival in patients with MM. Patients with relapsed and/or refractory MM can achieve objective responses with anti-BCMA CAR T cells. However, most patients, especially high-risk patients do not have disease remission lasting >18 months. A possible mechanism of resistance lies in antigen loss or down-regulation with the emergence of antigen-low or -negative subclones. We have mapped the cell surface proteome of Multiple Myeloma in search of suitable additional surface targets.

Lab Members

members of the perna lab

Titto A. Augustine, PhD, MSC

Assistant Research Professor of Medicine

Guiseppe Bombaci, PhD

Postdoctoral Fellow in Medicine

Annamaria Cesarano, MS

Research Associate in Medicine

Francesco Di Meo, PhD

Postdoctoral Fellow in Medicine

44344-Espinoza-Gutarra, Manuel

Manuel Espinoza-Gutarra, MD

Clinical Hematology/Oncology Fellow

portrait of victoria sanchez

Victoria Sanchez

Medical Student, William Wright Scholar

portrait of azka tasleem

Azka Tasleem, MD

Internal Medicine Resident

Join the Perna Lab

We are looking for smart and motivated scientists to join the Perna Lab. Students and postdoctoral fellows should email a CV to Dr. Perna.

Email Dr. Perna

Recent Lab News

November 19, 2021
The Perna Lab member Francesco Di Meo received a 2021 Abstract Achievement Award from the American Society of Hematology (ASH). The group will present an oral talk at the upcoming ASH Annual Meeting in December. 

September 27, 2021
Dr. Perna will present a talk entitled "Mapping the high-risk Multiple Myeloma cell surface proteome identifies T-cell inhibitory receptors for immune targeting" during the Interrogating the Tumor-Specific Surfaceome for Immune Targeting Virtual Workshop on September 29, hosted by the Society for Immunotherapy of Cancer.

team photo of the Perna lab at the Indianapolis Motor Speedway

September 9, 2021
Happy to share our collaboration with Yunlong Liu at IU School of Medicine demonstrating that intron retention generates a source of neoantigens and impacts survival of myeloma patients. We also showed that splicing inhibitors may regulate the abundance of MHC protein abundance in myeloma. Out today in Oncogene.

June 2021
During the summer of 2021, the Perna Lab will be hosting two summer research students.

May 30, 2021
The Perna Lab attended the Indianapolis 500!

 

Perna Lab in the Media

Lab-Details-19.jpg

What's Next in the Fight Against Myeloma?

IU School of Medicine recruited leading researchers and is studying how a patient’s personal factors and environment play a role in the disease.

IU Medicine Magazine | April 2020

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fabiana perna and her daughter

5 Questions with Fabiana Perna

Fabiana Perna, MD, PhD, focuses on developing novel immunotherapy by investigating the cancer cell surface proteome. In 2020, she was awarded a grant from IU School of Medicine and a one-year, $100,000 grant for new investigators from the Leukemia Research Foundation.

cancer.iu.edu | December 2020

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