פרופ' שי יזרעאלי

פדיאטריה סגל אקדמי קליני
ניווט מהיר:
פרופ' שי יזרעאלי
טלפון חיצוני: 03-9253669

Positions

Division of Pediatric Hematology and Oncology, Schneider Children's Medical Center;


Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine

 

Biography

Education

1975-1983 M.D. Degree - Medical School, Hebrew University, Jerusalem, Israel
1989-1993 Master Degree - Pediatrics, Tel Aviv University, Tel Aviv, Israel

 

Research

Basic and Translational and Research of Childhood Malignancies and Leukemia

We focus on patient-driven basic research into the pathogenesis of childhood leukemia and cancer. We harness advanced molecular and cellular biology technologies utilizing in-vitro and in-vivo models with the ultimate goal of improving the care of children with cancer.

 

Our research is divided into two major topics:

  1. Basic, translational and clinical research of leukemia.
  2. The role of SIL (STIL) protein in mitosis, centrosomal biology and cancer.

 

Cancer is the deadliest disease of children and leukemia is the most common childhood cancer. We are interested in the fundamental question how normal blood development is diverted into leukemia. What are the genetic and biochemical abnormalities that block cell differentiation, enhance proliferation and survival and confer the unique stem cell properties of self renewal to leukemia stem cells? We focus on chromosome 21 because of the mysterious association of leukemia with Down Syndrome. We utilize advanced genomic technologies, cell based assays of transformation of primary human and mouse stem cells, mouse models including transgenic, transplantation and explants of human leukemia. Our recent discoveries of the major involvement of the TSLP-IL7R-JAK2 pathway in leukemogenesis have lead to clinical trials with novel inhibitors of this pathway for high-risk leukemias in children and adults. The spread of leukemia to the brain is a major clinical problem as preventive therapy to the brain consistingof chemotherapy or irradiation causes long term side effects. We are therefore studying how leukemia cells spread to the central nervous system and developing mouse models to study this challenging problem.

 

We have discovered that SIL, a gene cloned from childhood leukemia, is required for centrosomal biogenesis and for survival of cancer cells. Targeting SIL by siRNA cause cancer cell death at mitotic entry in-vitro and in-vivo. Current research focuses on the fundamental role of the SIL protein in centrosome generation in normal and malignant cells and on developing approaches for its targeting for cancer therapy.

 

Publications & Grants

Publications

David, A., H. Amartely, N. Rabinowicz, M. Shamir, A. Friedler, and S. Izraeli. Molecular basis of the STIL coiled coil oligomerization explains its requirement for de-novo formation of centrosomes in mammalian cells. Sci Rep, 2016. 6: 24296.

 

Townsend, E.C., M.A. Murakami, A. Christodoulou, S. Izraeli, …J.C. Aster, M.A. Shipp, J.D. Griffin, and D.M. Weinstock. The public repository of xenografts enables discovery and randomized phase ii-like trials in mice. Cancer Cell, 2016. 29: 574-86.

 

Williams, M.T., Y.M. Yousafzai, A. Elder, K. Rehe, S. Bomken, L. Frishman-Levy, S. Tavor, P. Sinclair, K. Dormon, D. Masic, T. Perry, V.J. Weston, P. Kearns, H. Blair, L.J. Russell, O. Heidenreich, J.A. Irving, S. Izraeli, J. Vormoor, G.J. Graham, and C. Halsey. The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts. Blood, 2016. 127: 1998-2006.

 

Amar, D., T. Hait, S. Izraeli, and R. Shamir. Integrated analysis of numerous heterogeneous gene expression profiles for detecting robust disease-specific biomarkers and proposing drug targets. Nucleic Acids Res, 2015. 43: 7779-89.

 

Bugarin, C., J. Sarno, C. Palmi, A.M. Savino, G. te Kronnie, M. Dworzak, A. Shumich, B. Buldini, O. Maglia, S. Sala, I. Bronzini, J.P. Bourquin, E. Mejstrikova, O. Hrusak, D. Luria, G. Basso, S. Izraeli, A. Biondi, G. Cazzaniga, G. Gaipa, and I.B.s. group. Fine tuning of surface CRLF2 expression and its associated signaling profile in childhood B-cell precursor acute lymphoblastic leukemia. Haematologica, 2015. 100: e229-32.

 

Frishman-Levy, L., A. Shemesh, A. Bar-Sinai, C. Ma, Z. Ni, S. Frenkel, V. Muench, H. Bruckmueller, C. Vokuhl, K.M. Debatin, C. Eckert, M. Stanulla, M. Schrappe, K.S. Campbell, R. Loewenthal, D.M. Schewe, J. Hochman, L.H. Meyer, D. Kaufman, G. Cario, A. Porgador, and S. Izraeli. Central nervous system acute lymphoblastic leukemia: role of natural killer cells. Blood, 2015. 125: 3420-31.

 

Lellouche, E., L.L. Israel, M. Bechor, S. Attal, E. Kurlander, V.A. Asher, A. Dolitzky, L. Shaham, S. Izraeli, J.P. Lellouche, and S. Michaeli. MagRET nanoparticles: An iron oxide nanocomposite platform for gene silencing from micrornas to long noncoding RNAs. Bioconjug Chem, 2015. 26: 1692-701.

 

Mansour, M.R., C. Reed, A.R. Eisenberg, J.C. Tseng, J.C. Twizere, S. Daakour, A. Yoda, S.J. Rodig, N. Tal, C. Shochat, A. Berezovskaya, D.J. DeAngelo, S.E. Sallan, D.M. Weinstock, S. Izraeli, A.L. Kung, A. Kentsis, and A.T. Look. Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia. Br J Haematol, 2015. 168: 230-8.

 

Shaham, L., E. Vendramini, Y. Ge, Y. Goren, Y. Birger, M.R. Tijssen, M. McNulty, I. Geron, O. Schwartzman, L. Goldberg, S.T. Chou, H. Pitman, M.J. Weiss, S. Michaeli, B. Sredni, B. Gottgens, J.D. Crispino, J.W. Taub, and S. Izraeli. MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome. Blood, 2015. 125: 1292-301.

 

Tursky, M.L., D. Beck, J.A. Thoms, Y. Huang, A. Kumari, A. Unnikrishnan, K. Knezevic, K. Evans, L.A. Richards, E. Lee, J. Morris, L. Goldberg, S. Izraeli, J.W. Wong, J. Olivier, R.B. Lock, K.L. MacKenzie, and J.E. Pimanda. Overexpression of ERG in cord blood progenitors promotes  expansion and recapitulates molecular signatures of high ERG leukemias. Leukemia, 2015. 29: 819-27.

 

Tal, N., C. Shochat, I. Geron, D. Bercovich, and S. Izraeli. Interleukin 7 and thymic stromal lymphopoietin: from immunity to leukemia. Cell Mol Life Sci, 2014. 71:365-78.

 

Stary, J., M. Zimmermann, M. Campbell, L. Castillo, E. Dibar, S. Donska, A. Gonzalez, S. Izraeli, D. Janic, J. Jazbec, J. Konja, E. Kaiserova, J. Kowalczyk, G. Kovacs, C.K. Li, E. Magyarosy, A. Popa, B. Stark, Y. Jabali, J. Trka, O. Hrusak, H. Riehm, G. Masera, and M. Schrappe. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol, 2014. 32:174-84.

 

Meissner, B., T. Bartram, C. Eckert, J. Trka, R. Panzer-Grumayer, I. Hermanova, E. Ellinghaus, A. Franke, A. Moricke, A. Schrauder, A. Teigler-Schlegel, P. Dorge, A. von Stackelberg, G. Basso, C.R. Bartram, R. Kirschner-Schwabe, B. Bornhauser, J.P. Bourquin, G. Cazzaniga, J. Hauer, A. Attarbaschi, S. Izraeli, M. Zaliova, G. Cario, M. Zimmermann, S. Avigad, M. Sokalska-Duhme, M. Metzler, M. Schrappe, R. Koehler, G. Te Kronnie, and M. Stanulla, Frequent and sex-biased deletion of SLX4IP by illegitimate V(D)J-mediated recombination in childhood acute lymphoblastic leukemia. Hum Mol Genet, 2014. 23:590-601.

 

Izraeli, S., A. Vora, C.M. Zwaan, and J. Whitlock. How I treat ALL in Down's syndrome: pathobiology and management. Blood, 2014. 123:35-40.

 

Izraeli, S., C. Shochat, N. Tal, and I. Geron. Towards precision medicine in childhood leukemia - Insights from mutationally activated cytokine receptor pathways in acute lymphoblastic leukemia. Cancer Lett, 2014. 352:15-20.

 

Buitenkamp, T.D., S. Izraeli*, M. Zimmermann, E. Forestier, N.A. Heerema, M.M. van den Heuvel-Eibrink, R. Pieters, C.M. Korbijn, L.B. Silverman, K. Schmiegelow, D.C. Liang, K. Horibe, M. Arico, A. Biondi, G. Basso, K.R. Rabin, M. Schrappe, G. Cario, G. Mann, M. Morak, R. Panzer-Grumayer, V. Mondelaers, T. Lammens, H. Cave, B. Stark, I. Ganmore, A.V. Moorman, A. Vora, S.P. Hunger, C.H. Pui, C.G. Mullighan, A. Manabe, G. Escherich, J.R. Kowalczyk, J.A. Whitlock, and C.M. Zwaan*. Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood, 2014. 123:70-7.

 

Amartely, H., A. David, M. Lebendiker, H. Benyamini, S. Izraeli, and A. Friedler. The STIL protein contains intrinsically disordered regions that mediate its protein-protein interactions. Chem Commun (Camb), 2014. 50:5245-7.

 

Yoshida, K., T. Toki, Y. Okuno, R. Kanezaki, Y. Shiraishi, A. Sato-Otsubo, M. Sanada, M.J. Park, K. Terui, H. Suzuki, A. Kon, Y. Nagata, Y. Sato, R. Wang, N. Shiba, K. Chiba, H. Tanaka, A. Hama, H. Muramatsu, D. Hasegawa, K. Nakamura, H. Kanegane, K. Tsukamoto, S. Adachi, K. Kawakami, K. Kato, R. Nishimura, S. Izraeli, Y. Hayashi, S. Miyano, S. Kojima, E. Ito, and S. Ogawa. The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat Genet, 2013. 45:1293-9.

 

Meyer, C., et al. Izraeli, S. et al and R. Marschalek. The MLL recombinome of acute leukemias in 2013. Leukemia, 2013. 27:2165-76.

 

Goldberg, L., M.R. Tijssen, Y. Birger, R.L. Hannah, S.J. Kinston, J. Schutte, D. Beck, K. Knezevic, G. Schiby, J. Jacob-Hirsch, A. Biran, Y. Kloog, G. Marcucci, C.D. Bloomfield, P.D. Aplan, J.E. Pimanda, B. Gottgens, and S. Izraeli, Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia. Blood, 2013. 122:2694-703.

 

Castiel, A., L. Visochek, L. Mittelman, Y. Zilberstein, F. Dantzer, S. Izraeli, and M. Cohen-Armon. Cell death associated with abnormal mitosis observed by confocal imaging in live cancer cells. J Vis Exp, 2013. 78:e50568.

 

Birger, Y., L. Goldberg, T.M. Chlon, B. Goldenson, I. Muler, G. Schiby, J. Jacob-Hirsch, G. Rechavi, J.D. Crispino, and S. Izraeli. Perturbation of fetal hematopoiesis in a mouse model of Down syndrome's transient myeloproliferative disorder. Blood, 2013. 122:988-98.

 

Auer, F., F. Ruschendorf, M. Gombert, P. Husemann, S. Ginzel, S. Izraeli, M. Harit, M. Weintraub, O.Y. Weinstein, I. Lerer, P. Stepensky, A. Borkhardt, and J. Hauer. Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A. Leukemia, 2013. 28:1136-8.

 

Birger, Y., L. Goldberg, T.M. Chlon, B. Goldenson, I. Muler, G. Schiby, J. Jacob-Hirsch, G. Rechavi, J.D. Crispino, and S. Izraeli. Perturbation of fetal hematopoiesis in a mouse model of Down syndrome's transient myeloproliferative disorder. Blood, 2013. 122:988-98.

 

 

 

Reviews

Izraeli, S., The acute lymphoblastic leukemia of Down Syndrome - Genetics and pathogenesis. Eur J Med Genet, 2016. 59:158-61.

 

Savino, A.M. and S. Izraeli, On mice and humans: the role of thymic stromal lymphopoietin in human B-cell development and leukemia. Haematologica, 2016. 101: 391-3.

 

Pui, C.H., J.J. Yang, S.P. Hunger, R. Pieters, M. Schrappe, A. Biondi, A. Vora, A. Baruchel, L.B. Silverman, K. Schmiegelow, G. Escherich, K. Horibe, Y.C. Benoit, S. Izraeli, A.E. Yeoh, D.C. Liang, J.R. Downing, W.E. Evans, M.V. Relling, and C.G. Mullighan. Childhood Acute Lymphoblastic Leukemia: Progress through collaboration. J Clin Oncol, 2015. 33: 2938-48.

 

Tal, N., C. Shochat, I. Geron, D. Bercovich, and S. Izraeli. Interleukin 7 and thymic stromal lymphopoietin: from immunity to leukemia. Cell Mol Life Sci, 2014. 71:365-78.

 

 

Grants

  • 2014-2017 EU ERA-NET TRANSCANCER “TRANSALL” Validation of biomarkers for the diagnosis and risk stratification of childhood ALL
  • 2014-2018 BSF Functional analysis of ERG GATA1
  • 2014-2018 ISF Modelling T-lympho-myeloid leukemia
  • 2014-2017 ISF-NSFC Hematopoietic transcription factors in leukemia – mouse models and human leukemias
  • 2014-2017 The Israel Science Foundation (ISF) and the National Natural Science Foundation of China (NSFC), PIs Izraeli, Shai (Israel) Chen, Sai-Juan (China)
  • 2014-2017 Israel Ministry of Health ERA-NET EU programs, PIs Izraeli, Shai (Israel), multiple Europeans PIs
  • 2014-2018 Israel Science Foundation
  • 2014-2018 USA-Israel Bi-National Scientific Foundation, PIs Izraeli, Shai (Israel); Crispino, John (USA)
  • 2015-2018 DOD USAMRMC
  • 2016-2018 Children With Cancer UK, PI Enver, Tariq (UCL), co-PI Izraeli, Shai
  • 2016-2019 German Israel Foundation

 

אוניברסיטת תל-אביב, ת.ד. 39040, תל-אביב 6997801
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