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Disclosures: NO DISCLOSURE ON FILE OMB No. 0925-0046, Biographical Sketch Format Page OMB No. 0925-0001 and 0925-0002 (Rev. 10/2021 Approved Through 09/30/2024) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Kim E. Nichols, MD eRA COMMONS USER NAME (credential, e.g., agency login): NICHOLSKE POSITION TITLE: Full Member, St. Jude Children’s Research Hospital EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) INSTITUTION AND LOCATION | DEGREE (if applicable) | Completion Date MM/YYYY | FIELD OF STUDY | Dartmouth College, Hanover NH | B.A. | 06/1984 | Biology | Duke University School of Medicine, Durham NC | M.D. | 06/1989 | Medicine | Children’s Hospital, Boston MA | Residency | 06/1992 | Pediatrics | Dana-Farber Cancer Institute, Boston MA | Fellowship | 06/1995 | Pediatric Oncology | Massachusetts General Hospital, Boston MA | Post-Doc. | 01/2000 | Molecular Genetics |
A. Personal Statement I am a pediatric oncologist with 25 years of clinical and research experience in hemophagocytic lymphohistiocytosis (HLH) and related disorders of the immune system. Currently, I am a Full Member in the Department of Oncology at St. Jude Children’s Research Hospital (St. Jude), where I also serve as Director of the Division of Cancer Predisposition and founding member of the St. Jude Histiocytosis and Immune Dysregulation Treatment Team. In my research laboratory, we use animal models to decipher the cellular and molecular mechanisms driving inflammation in HLH and using the information gained to develop new and improved therapies for affected children. In addition to my duties at St. Jude, I am a member of the American Society for Pediatric Hematology Oncology Clinical Immunology Special Interest Group, Executive and Steering Committees for the North American Consortium for Histiocytosis (a St. Baldrick’s funded research consortium with the mission to cure all patients with histiocytic diseases [including HLH] and optimize outcomes through innovative and collaborative research), and an active member of the Histiocyte Society (an international professional community of physicians and scientists committed to education, clinical care and research on the histiocytic disorders). Within the Histiocyte Society, I serve as President, member of the Executive Board, past-Chair of the HLH Steering Committee, and past-member of the Scientific and Education Committees. B. Positions, Scientific Appointments and Honors Positions and Scientific Appointments
2022 - | President, Histiocyte Society | 2020 - | Member, American Society for Pediatric Hematology Oncology (ASPHO) | 2020 - | Member, ASPHO Clinical Immunology Special Interest Group | 2020 - | Co-Lead, ASPHO Cancer Predisposition Special Interest Group | 2019 - 2023 | Chair, HLH Steering Committee, Histiocyte Society | 2014 - | Member, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN | 2014 - | Member, Executive Board, Histiocyte Society | 2014 - | Member, Executive Committee, North American Consortium for Histiocytosis | 2013 - 2017 | Member, Scientific Committee on Immunology & Host Defense, Am. Society of Hematology | 2013 - 2023 | Member, HLH Steering Committee, Histiocyte Society | 2011 - | Member, American Society of Hematology | 2007 - 2014 | Associate Professor, Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia PA | 2003 - 2009 | Member, Education Committee, Histiocyte Society | 2000 - 2008 | Member, Steering Committee, Nikolas Symposia on the Histiocytoses | 2000 - 2007 | Assistant Professor, Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia PA | 1999 - 2001 | Member, Scientific Committee, Histiocyte Society | 1995 - 2000 | Instructor, Pediatrics, Boston Children's Hospital, Boston, MA |
Honors 2022 | Jeffrey Toughill Prize for best grant application, Histioctye Society | 2013 - 2018 | Member, Hematology Oncology Sub-board, American Board of Pediatrics | 2013 | Innovation Award, CHOP CCCR - Alex’s Lemonade Stand Foundation | 2013 | Nezelof Prize in Basic Science, Histiocyte Society | 2011 | Elected Member, Society for Pediatric Research | 2002 | Junior Faculty Scholar Award, American Society of Hematology | 1999 | Selected for Artemis Fellowship, Nikolas Symposium | 1995 - | Member, Histiocyte Society | 1995 | Career Development Award (Declined), American Cancer Society Clinical Oncology | 1989 | Member, Alpha Omega Alpha, Duke University School of Medicine | 1984 | Member, Phi Beta Kappa, Dartmouth College | 1984 | Summa Cum Laude, Dartmouth College |
C. Contributions to Science My major contributions to science include those in which I have identified the genetic basis for several human Mendelian disorders associated with primary immunodeficiency and/or cancer and then used this information to elucidate the underlying disease mechanisms and develop new diagnostic and treatment approaches.
1. Identification and characterization of the X-linked lymphoproliferative (XLP) disease gene: A major focus of my laboratory research has been the study of XLP, a rare, poorly understood, and often-fatal primary immune deficiency associated with increased susceptibility to Epstein Barr virus (EBV), B-cell lymphoma and hypogammaglobulinemia. As a postdoctoral fellow, I was among the first to discover that XLP is caused by germline mutations in SH2D1A (also known as DSHP), the gene encoding a small adaptor protein known as Signaling Lymphocytic Activation Molecule (SLAM)-associated protein (SAP). Over the last two decades, my laboratory has worked to rigorously examine how this adaptor regulates immune cell development and function and coordinates host immunity to EBV. Through these studies, we have defined key roles for SAP during natural killer cell cytotoxicity, CD4 T cell “help” to B cells, invariant natural killer T (iNKT) cell ontogeny and cytotoxic function, and T cell apoptosis. Most recently, we reported on an altered signaling pathway in XLP and described the therapeutic effects of a novel drug targeting the critical enzyme diacylglycerol kinase alpha, which shows promise in curtailing hyper-inflammation in murine XLP models. - Nichols KE, Harkin DP, Levitz S, Krainer M, Kolquist A, Gresko C, Bernard A, Ferguson M, Zuo L, Snyder E, Buckler AJ, Wise C, Ashley J, Lovett M, Valentine M, Look AT, Housman DE, Haber DA. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proceedings of the National Academy of Science USA, 1998; 95:13765-13770. PMCID: PMC24894
- Nichols KE, Hom J, Gong S-Y, Ganguly A, Ma C, Cannons J, Tangye SG, Schwartzberg PL, Koretzky GA, Stein PL. Regulation of NKT cell development by SAP, the protein defective in X-linked lymphoproliferative disease. Nature Medicine, 2005; 11(3): 340-345. PMID: 15711562
- Das R, Bassiri H, Guan P, Wiener S, Banerjee P, Zhong M-C, Veillette A, Orange JS, Nichols KE. The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation. Blood, 2013; 121(17):3386-3395. PMCID: PMC3637014
- Ruffo E, Malacarne V, Larsen SE, Das R, Patrussi L, Wülfing C, Biskup C, Kapnick SM, Verbist K, Tedrick P, Schwartzberg PL, Baldari CT, Rubio I, Nichols KE*, Snow AL*, Baldanzi G*, Graziani A*.. Inhibition of diacylglycerol kinase alpha restores restimulation-induced cell death and reduces immunopathology in XLP. Science Translational Medicine, 2016; 8(321):321ra7. *Equal contribution. PMCID: PMC4918505
2. Defining the pathogenesis and developing new treatments for hemophagocytic lymphohistiocytosis (HLH): HLH is a severe hyper-inflammatory syndrome typified by the excessive activation of cytotoxic T cells and macrophages that copiously produce numerous pro-inflammatory cytokines. Through my studies of XLP, which has a similar clinical phenotype, I have developed a strong interest in the pathogenesis and treatment of primary (inherited; genetic) and secondary (acquired) HLH. Despite current standard-of-care approaches, up to 40% of all HLH patients die due to the disease. Those that survive often experience poor quality of life due to recurrent bouts of inflammation, leading to hospitalization. In my laboratory, we use mouse pre-clinical models to understand the cellular and molecular mechanisms underlying development of HLH and to test the therapeutic effects of novel drugs and drug combinations. From these studies, we take promising agents forward in the form of clinical trials for children and adults with HLH. Towards this end, I currently serve as co-Principal Investigator on a prospective multi-institutional clinical trial that emerged from pre-clinical studies carried out in my laboratory, which examines the tolerability and efficacy of a response adapted ruxolitinib-containing regimen for children with newly diagnosed or relapsed/refractory HLH (NCT04551131). - Spessott WA, Sanmillan ML, McCormick ME, Patel N, Villanueva J, Zhang K, Nichols KE*, Giraudo CG. Hemophagocytic lymphohistiocytosis caused by dominant negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion. Blood, 2015; (10):1566-77. *Co-corresponding author PMCID: PMC4351505
- Das R, Guan P, Sprague L, Verbist K, Tedrick P, An Q, Cheng C, Kurachi M; Levine R, Wherry EJ, Canna SW, Behrens EM, Nichols KE. Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. Blood, 2015; 127(13):1666-75. PMCID: PMC4817310.
- Albeituni S, Verbist KC, Tedrick PE, Tillman H, Picarsic J, Bassett R, Nichols KE. Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis. Blood, 2019. Apr 23. pii: blood.2019000761. doi: 10.1182/blood.2019000761. PMID: 31015190
- Meyer L, Verbist KC, Albeituni S, Scull BP, Bassett R, Stroh AN, Tillman H, Allen CE, Hermiston M, Nichols KE. JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation. Blood, 2020; 136(6):657-668. PMCID: PMC7414590 * plenary paper
3. Elucidating the germline and tumor genomic factors underlying development of childhood cancer: Since joining the faculty at St. Jude in 2014, much of my work has focused on defining the prevalence and spectrum of germline and somatic mutations in childhood cancer. Using whole exome (WES) and genome sequencing (WGS) to evaluate more than 1,000 pediatric oncology patients, I and my colleagues reported that at least 1 in 10 children with cancer harbor pathogenic germline mutations in a cancer predisposing gene. We are currently extending these studies to define how germline mutations influence presentation, tumor pathology, response to therapy and long-term outcomes. We have recently published the results of the Genomes for Kids research study, which used comprehensive WES, WGS and RNA sequencing to interrogate the tumor and/or germline genomic landscapes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically-relevant (25%), and/or cancer predisposing (18%) variants. Evaluation of tumor-normal data revealed relevance to tumor development for 55% of pathogenic germline variants. In parallel to these genomic studies, I and my research team have carried out exploratory investigations of parent and provider understanding of tumor and germline genomics and the factors that influence parent decision making around germline genetic testing of children with cancer. Overall, these studies have had an impact by better defining the germline genetic factors that contribute to childhood cancer risk and the tumor genetic factors that may better inform cancer treatment approaches. - Zhang J*, Walsh MF*, Wu G*, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, Weaver MS, Ding L, Mardis ER, Wilson RK, Gajjar A, Ellison DW, Pappo AS, Pui C-H, Nichols KE*, Downing JR*. Germline Mutations in Predisposition Genes in 1,120 Children with Cancer; New England Journal of Medicine, 2015; 373(24):2336-46. *Equal contribution. PMCID: PMC4734119
- Johnson LM, Sykes A, Shaohua L, Valdez JM, Gattuso J, Gerhardt E, Hamilton KV, Harrison LW, Hines-Dowell S, Jurbergs N, McGee RB, Nuccio R, Ouma AA, Pritchard M, Quinn E, Baker JN, Mandrell BN, Nichols KE. Speaking Genomics to Parents Offered Germline Testing for Cancer Predisposition. Cancer, 2019; 125(14):2455-2464. PMID: 30901077.
- Howard Sharp KM, Jurbergs N, Ouma A, Harrison L, Gerhardt E, Taylor L, Hamilton K, McGee RB, Nuccio R, Quinn E, Hines-Dowell S, Kesserwan C, Sunkara A, Gattuso J, Pritchard M, Mandrell B, Relling MV, Haidar CE, Kang G, Johnson L, Nichols KE. Predicting families who decline participation in a pediatric oncology next generation sequencing study. JCO Precision Oncology, 2020; 4:202-211. PMCID: PMC7213582
- Newman S, Nakitandwe J, Kesserwan CA , Azzato EM, Wheeler DA, Rusch MC, Shurtleff S, Hedges DJ, Hamilton KV, Foy SG, Edmonson MN, Thrasher A, Bahrami A, Orr BA, Klco JM, Gu J, Harrison LW, Wang L, Clay M, Ouma A, Silkov A, Liu Y, Zhang Z, Liu Y, Brady S, Zhou X, Chang T, Pande M, Davis E, Becksfort J, Patel A, Wilkinson M, Rahbarinia D, Kubal M, Maciaszek JL, Pastor V, Knight J, Gout A, Wang J, Gu Z, Mullighan CG, McGee RB, Quinn EA, Nuccio R, Mostafavi R, Gerhardt EL, Taylor LM, Valdez JM, Hines Dowell SJ, Pappo A, Robinson G, Johnson LM, Pui C, Ellison DW, Downing JR, Zhang J, Nichols KE. Genomes for Kids: The scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discovery, 2021; July 23:candisc.1631.2020. doi: 10.1158/2159-8290.CD-20-1631. Online ahead of print. PMID: 34301788
4. Genetic predisposition to hematologic disorders. In addition to XLP, I have isolated the genes responsible for two other human diseases associated with impaired development and/or function of hematopoietic cells, including GATA1-related X-linked cytopenia and ETV6 related predisposition to childhood B-ALL (also known as Thrombocytopenia 5). Through this work, I aim to gain a better understanding of the underlying disease mechanisms and use this information to improve diagnosis and management of future children and families affected by these disorders. Currently, I serve as the PI on an NCI-funded R01 in which we will use primary human samples, engineered human induced pluripotent stem cell lines and genetic mouse models to decipher how germline defects in ETV6 impair hematopoiesis and promote B-leukemogenesis. - Nichols KE, Crispino JD, Poncz M, White JG, Orkin SH, Maris JM, Weiss MJ. Familial dyserythropoietic anemia and thrombocytopenia due to an inherited mutation in GATA1. Nature Genetics 2000; 24(3):266-270. PMID: 10700180.
- Topka S, Vijai J, Walsh MF, Jacobs L, Maria A Villano D, Gaddam P, Wu G, McGee RB, Quinn E, Inaba H, Hartford C, Pui CH, Pappo AS, Edmonson M, Zhang M, Stepensky P, Steinherz P, Schrader K, Lincoln A, Bussel J, Lipkin S, Goldgur Y, Harit M, Stadler ZK, Mullighan C, Weintraub M, Shimamura A, Zhang J, Downing JR, Nichols KE*, Offit K*. Germline ETV6 mutations confer susceptibility to acute lymphoblastic leukemia and thrombocytopenia. PLoS Genetics, 2015; 11(6):e1005262. *Co-senior, co-corresponding author PMCID: PMC4477877
- Moriyama T, Metzger ML, Wu G, Nishii R, Qian M, Devidas M, Yang W, Cheng C, Quinn E, Raimondi S, Gastier-Foster JM, Raetz E, Larsen E, Martin PL, Bowman WP, Winick N, Komada Y, Wang S, Edmonson M, Xu H, Mardis E, Fulton R, Pui C-H, Mullighan C, Evans WE, Zhang J, Hunger SP, Relling MV, Nichols KE, Loh ML, Yang JJ. Germline Genetic Variation in ETV6 and Risk of Childhood Acute Lymphoblastic Leukemia: a Systematic Genetic Study; Lancet Oncology, 2015; 16(16):1659-66. PMCID: PMC4684709
- Nishii R, Baskin-Doerfler R, Yang W, Oak N, Zhao X, Yang W, Hoshitsuki K, Bloom M, Verbist K, Burns M, Li Z, Lin TN, Qian M, Moriyama T, Gastier-Foster JM, Rabin KR, Raetz E, Mullighan C, Pui CH, Yeoh AEJ, Zhang J, Metzger ML, Klco JM, Hunger SP, Newman S, Wu G, Loh ML, Nichols KE, Yang JJ. Molecular Basis of ETV6-Mediated Predisposition to Childhood Acute Lymphoblastic Leukemia. Blood, 2021; 137(3):364-373. PMCID: PMC7819760 Role: Co-corresponding author
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