Iannis Aifantis, PhD

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Professor and Chair of Pathology
Early Career Scientist,
Howard Hughes Medical Institute
Ph.D., 1999 University of Paris V/Necker Institute

LAB WEBSITE:
Aifantis Lab
RESEARCH THEMES:
Cancer Stem Cells, Developmental Immunology, Hematopoiesis, Stem Cel Biology
KEYWORDS:
Hematopoiesis, Stem cells, Ubiquitination, Self-Renewal, Cell cycle progression

Contact Information
New York University School of Medicine
Howard Hughes Medical Institute
Dept. of Pathology, SRB 1304
522 First Ave. New York, NY 10016
Tel: (212) 263-9898
 E-mail: Iannis.Aifantis@med.nyu.edu
Admin Contact

 

Michelle Wicinski
Executive Assistant
212-263-9898

Genetic and genomic studies addressing the balance between physiological stem cell differentiation and transformation leading to cancer.

 

Molecular Mechanisms of Stem Cell Self-Renewal, Differentiation and Transformation

A) The role of the Fbw7 E3 ubiquitin ligase in hematopoietic stem cell function and leukemia

We would like to understand how the E3 Ubiquitin Ligase, Fbw7, as a regulator of post-transcriptional regulation of protein stability, could regulate hematopoietic stem cell fate decisions. Fbw7 is a potent tumor suppressor as it regulates several proto-oncogenes such as c-Myc, Notch and CyclinE. Work from our lab has concluded that Fbw7 indeed has a physiological role in hematopoiesis. We have confirmed the tumor suppressor role of Fbw7 as conditional ablation of Fbw7 in the hematopoietic compartment leads to T-cell acute lymphoblastic leukemia.  However, a significant percentage of mice succumb to anemia before tumor development occurs suggesting an alternative function for Fbw7 in normal hematopoiesis.  Indeed, we observed a severe loss of hematopoietic stem cells upon deletion of Fbw7 in hematopoietic compartment. Our lab has addressed the contribution of two well characterized Fbw7 substrates, c-Myc and Notch, to the Fbw7-/- HSC defect.  We found that relative c-Myc protein stability (and not Notch) was essential for regulating HSC self-renewal and differentiation. Interestingly, Fbw7 was dispensible for self-renewing embryonic stem cells. This work demonstrated, for the first time, that the ubiquitin proteasome system is a novel regulator of HSC function. Furthermore, it suggested that the Fbw7:substrate interaction can be interpreted differently in stem cells from different ages.  At least two interesting questions have emerged from these studies; How do Fbw7:substrate interactions impact stem cell fate decisions over time (i.e during aging)? Do Fbw7:substrate interactions contribute to stem cell-driven malignancies?

B) Notch signaling in hematopoietic stem cell differentiation

Hematopoiesis is a complex process that requires coordination between self-renewal, and differentiation of stem and progenitor cells to generate mature cells in the blood. Notch signaling has been implicated in the regulation of these diverse functions in the hematopoietic system and other tissues. Whereas the importance of Notch1 in lymphocyte development and oncogenic transformation has been well characterized, the relevance of Notch in the specification of other hematopoietic lineages and hematopoietic stem cell (HSC) function remains unclear.

We performed lineage-tracing experiments in early hematopoietic progenitors to determine the fate of Notch receptor expressing cells within the hematopoietic system using transgenic mice with tamoxifen inducible CreER “knocked in” the locus of each Notch receptor. Crossing these animals to the ROSA26-tdRFP reporter permits the irreversible labeling of hematopoietic cells expressing a given Notch receptor and their progeny. To address whether these receptors were being activated, we analyzed Hes1-eGFP knock-in animals (Hes1GFP/+). Hes1, a bHLH repressor, is a well-characterized transcriptional target of intracellular Notch. We found that GFP expression in these mice faithfully recapitulates Notch signaling and that there are distinct subsets of hematopoietic progenitors that have activation of the Notch pathway. In addition, we are using these and other novel genetic tools to further characterize Notch signaling within bone marrow stem cell niches using in vivo imaging.

Hes1 is also of special interest because it could be a key mediator of cell fates through its influence on transcription factor networks. For example, the promoters of the myeloid transcription factors PU.1 and CEBP/a genes both contain Hes1 binding sites known as the “N-box”. Interestingly, their expression is increased upon Notch loss-of-function and decreased with Notch gain-of-function. By combining lineage tracing, Notch reporters, imaging, and deep sequencing we will complete the fragmented picture of Notch receptor expression and signaling during bone-marrow hematopoiesis. This work will provide insights into the normal developmental role of Notch in hematopoietic cells and highlight how Notch-Hes1 may act during oncogenic transformation.

C) Proteomic landscapes in stem cell differentiation and cancer

Currently, we are developing proteomic approaches to delineate the role of the ubiquitin proteasome system (UPS) in hematopoiesis, cancer and stem cell function. For that purpose, we mainly focus on the E3 ligase Fbw7, which regulates the degradation of several important oncogenes with central roles in cell division, growth and differentiation. We have recently shown that Fbw7 acts as a tumor suppressor of T-cell acute lymphoblastic leukemia (T-ALL) by targeting Notch1. Furthermore, we have shown that, by targeting c-Myc, Fbw7 regulates the quiescence and self-renewal capacity of hematopoietic stem cells (HSCs); however, it is dispensable for pluripotency of embryonic stem cells (ESC), but appears to acquire a role along with cell differentiation.

We are now working on the identification of novel Fbw7 substrates by in-vitro tandem purifications combined with mass spectrometry. We then want to understand the role that the newly identified Fbw7:substrate pairs have in the different considered systems. In addition, we are developing strategies to perform global mass spectrometry analysis of various types of cells in which Fbw7 has been deleted by genetic engineering in order to identify additional substrates by comparing them to their controls. For these series of experiments, we include in vivo and in vitro models aiming to define the tissue and function specificity of the landscape of Fbw7 substrates. After these experiments we should be able to answer question such as: Which are the Fbw7 substrates involved in stem cell differentiation? or Which Fbw7 substrates are upregulated after Fbw7 malfunctioning in different types of cancer? Altogether, the ultimate goal of our research is to identify pathways that are new potential therapeutic targets in leukemia and, possibly, in other types of cancer.

Selected Publications: 
  • Strikoudis A, Guillamot M, Aifantis I. Regulation of stem cell function by protein ubiquitylation. EMBO Rep, 2014. PMID: 24652853
  • Ntziachristos P, Lim JS, Sage J, Aifantis I. From fly wings to targeted cancer therapies: a centennial for notch signaling.  Cancer Cell (Cell Press), 2014. PMID: 24651013
  • Lobry C, Oh P, Mansour MR, Look AT, Aifantis I. Notch signaling: switching an oncogene to a tumor suppressor. Blood, 2014. PMID: 24608975
  • Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR, Kuscu C, Hricik T, Ndiaye-Lobry D, Lafave LM, Koche R, Shih AH, Guryanova OA, Kim E, Li S, Pandey S, Shin JY, Telis L, Liu J, Bhatt PK, Monette S, Zhao X, Mason CE, Park CY, Bernstein BE, Aifantis I, Levine RL. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med, 2013. PMID: 24218140
  • Poulos MG, Guo P, Kofler NM, Pinho S, Gutkin MC, Tikhonova A, Aifantis I, Frenette PS, Kitajewski J, Rafii S, Butler JM. Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis. Cell Rep, 2013. PMID: 24012753
  • Chaumeil J, Micsinai M, Ntziachristos P, Roth DB, Aifantis I, Kluger Y, Deriano L, Skok JA. The RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage. Nature Communications, 2013. PMID: 23900513
  • Trimarchi T, Ntziachristos P, Aifantis I. A new player SETs in myeloid malignancy. Nature Genetics. 2013. PMID: 23892662
  • Oh P, Lobry C, Gao J, Tikhonova A, Loizou E, Manet J, van Handel B, Ibrahim S, Greve J, Mikkola H, Artavanis-Tsakonas S, and Aifantis I. In vivo mapping of Notch pathway activity in normal and stress hematopoiesis. Cell Stem Cell, 13(2):190-204, 2013.  PMID: 23791481
  • King B, Trimarchi T, Reavie L, Xu L, Mullenders J, Ntziachristos P, Aranda-Orgilles B, Perez-Garcia A, Shi J, Vakoc C, Sandy P, Shen SS, Ferrando A and Aifantis I. The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. Cell, 153(7): 1552-1566, 2013. PMID: 23791182
  • Reavie L, Buckley SM, Loizou E, Takeishi S, Aranda-Orgilles B, Ndiaye-Lobry D, Abdel-Wahab O, Ibrahim S, Nakayama KI and Aifantis I. Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell, 23(3):362-375, 2013.  PMID: 23518350
  • Lobry C, Ntziachristos P, Ndiaye-Lobry D, Oh P, Cimmino L, Hu W, Abdel-Wahab O, Ibrahim S, Skokos D, Armstrong SA, Levine RL, Park CY and Aifantis I. Notch pathway activation targets AML initiating cell homeostasis and differentiation. The Journal of Experimental Medicine, 210(2): 301-19, 2013. PMID: 23359070
  • Buckley SM, Aranda-Orgilles B, Strikoudis A, Apostolou E, Loizou E, Moran-Crusio K, Farnsworth CL, Dasgupta R, Silva JC, Stadtfeld M, Hochedlinger K, Chen E, and Aifantis I. Regulation of pluripotency and cellular reprogramming by the ubiquitin proteasome system. Cell Stem Cell, 11(6):783-98, 2012. PMID: 23103054
  • Sawai C, Freund J, Ndyiae-Lobry D, Oh P, Bretz JC, Strikoudis A, Genesca L, Trimarchi T, Kelliher MA, Clark M, Soulier J, Chen-Kiang S, and Aifantis I. Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia. Cancer Cell, 22(4):452-465, 2012. PMID: 23079656
  • Ntziachristos P, Tsirigos A, van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS, Ferres-Marco D, da Ros V, Tang Z, Siegle J, Huynh T, Utro F, Poglio S, Samon JB, Levine RL, Brown S, Pflumio F, Dominguez M, Ferrando A, and Aifantis I. Genetic Inactivation of the PRC2 Complex in T-Cell Acute Lymphoblastic Leukemia. Nature Medicine, 18(2): 298-303, 2012. PMID: 22237151
  • Billiard F, Lobry C, Darrasse-Jèze G, Waite J, Liu X, Mouquet H, DaNave A, Tait M, Idoyaga J, Leboeuf M, Kyratsous CA, Burton J, Kalter J, Klinakis A, Zhang W, Thurston G, Merad M, Steinman RM, Murphy AJ, Yancopoulos GD, Aifantis I, Skokos D. Dll4-Notch signaling in Flt3-independent dendritic cell development and autoimmunity in mice. J Exp Med. 2012 May 7;209(5):1011-28. PMID: 22547652
  • King B, Ntziachristos P, Aifantis I. (2012) Hijacking T cell differentiation: new insights in TLX function in T-ALL. Cancer Cell. 2012 Apr 17;21(4):453-5. PMID: 22516255
  • Moran-Crusio K, Reavie LB, Aifantis I. (2012) Regulation of hematopoietic stem cell fate by the ubiquitin proteasome system. Trends Immunol. 2012 Jul;33(7):357-63. PMID: 22349458
  • Moran-Crusio, K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, Figueroa ME, Vasanthakumar A, Patel J, Zhao X, Perna F, Pandey S, Song C, He C, Madzo J, Dai 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, 20(1): 11-24, 2011. (*Dr. Aifantis is the equal corresponding and senior author). PMID: 21723200
  • Klinakis* A, Lobry* C, Abdel-Wahab, Oh P, Haeno H, Buonamici S, van de Walle I, Cathelin S, Trimarchi T, Araldi E, Liu S, Ibrahim S, Beran M, Zavadil J, Efstratiadis A, Taghon T, Michor F, Levine R, and Aifantis I. A novel tumor suppressor function for the Notch pathway in myeloid leukemia. Nature, 473 (7346):230-3, 2011. PMID: 21562564
  • Germar K, Dose M, Konstantinou T, Zhang J, Wang H, Lobry C, Arnett KL, Blacklow SC, Aifantis I, Aster JC, Gounari F. (2011) T-cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling. Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20060-5. PMID: 22109558
  • Lobry C, Oh P, Aifantis I. (2011) Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think.  J Exp Med. Sep 26;208(10):1931-5. PMID: 21948802
  • Cimmino L, Abdel-Wahab O, Levine RL, Aifantis I. (2011) TET Family Proteins and their role in stem cell differentiation and transformation.  Cell Stem Cell. Sep 2;9(3):193-204. PMID: 21885017
  • Espinosa L, Cathelin S, D’Altri T, Trimarchi T, Statnikov A, Guiu J, Rodilla V, Ingles-Esteve J, Nomdedeu J, Bellosillo B, Kucine N, Sun S-C, Song G, Mullighan C, Levine RL, Rajewsky K, Aifantis I*, Bigas A*. (2010) The Notch/Hes1 pathway sustains NF-kB activation through CYLD repression in T cell leukemia. Cancer CELL, 18(3): 268-81. (*Dr. Aifantis is the corresponding author and equal senior author). PMID: 20832754
  • Crusio KM, King B, Reavie LB, and Aifantis I. (2010) The ubiquitous nature of cancer: The role of the SCF(Fbw7)complex in development and transformation. Oncogene, 29(35): 4865-73. PMID: 20543859
  • Reavie L, Della Gatta G, Thomson B, Palomero T, Bredemeyer AL, Helmink BA, Zavadil J, Sleckman BP, Ferrando A and Aifantis I. (2010) Hematopoietic Stem Cell Quiescence Regulated by a Single Ubiquitin Ligase: Substrate Complex. Nature Immunology, 11:207-215. PMID: 20081848