Research Topics

Our Research is divided into two major aspects:

1) Deciphering the pathogenesis of childhood leukemia - This major focus of our laboratory is headed by Dr Yehudit Birger. Currently we focus on the following themes:

(a) The leukemias of Down Syndrome as a model for childhood leukemia.

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Leukemias, like every cancer, are caused by changes in the DNA which include changes in the structure or number of the chromosomes. Extra copy of chromosome 21 is often found in leukemias. Children with Down syndrome have an extra chromosome 21 in their normal cells and have a marked increase in the risk of developing leukemia. We therefore study the leukemias of Down Syndrome with the ultimate goal of identify and characterize abnormalities associated with chromosome 21 leukemias in children. These studies have already lead to important discoveries (1, 2) such as the GATA1 mutations in the myeloid leukemias of Down Syndrome(3), the cooperation with the chromosome 21 transcription factor ERG in myeloid leukemias of Down Syndrome(4)(5) and the involvement of JAK2 in the lymphoid leukemias(6). Our discoveries are important not only for patients with Down Syndromes but for all patients with leukemia. For example the mutations in JAK2 we discovered are important for many children with incurable leukemia, and ERG has been shown to be an important leukemia and prostate cancer oncogene. This discovery may lead to specific therapies of these leukemias. Furthermore, elucidation of the role of trisomy 21 in leukemia may contribute to the general understanding of the role of chromosomal aneuploidy in cancer (7).

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(b) The Genetic Basis of Brain Metastasis in Leukemia and Solid Tumors: Metastasis to the brain is one of the most devastating complications of cancer and of childhood leukemia. To prevent this complication most children get either irradiation or intra-spinal chemotherapy with long lasting effects on neuropsychological functions. We want to find the factors that determine specific spread of cancer cells to the brain in order to personalize treatment to high risk patients and to provide a base for novel more specific less toxic therapies. To approach this challenging problem we use genomic, cell culture and mouse models. Initial studies identified three genes predicting brain metastasis of lung cancer(8) and, in a collaborative study with the BFM group in Germany, that increased expression of interleukin 15 in primary leukemia cells is associated with increased spread to the central nervous system(9).

(c) MicroRNAs and non-coding RNAs in childhood leukemia. We are studying the role of these newly described genes in childhood leukemia. In a collaborative study with the University of Dusseldorf, we have recently discovered the involvement of a microRNA, miR125b, in providing survival advantage to the most common childhood leukemia containing the TEL/AML1 translocation (Gefen et al. leukemia, in press)

(d) Clinical studies of childhood acute lymphoblastic leukemia (ALL): Prof Shai Izraeli is the co-chair of the Israel National Study of childhood ALL.

2) The SIL (STIL) gene as a regulator of mitosis and survival of cancer:

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S The SIL (SCL TAL1 Interrupting Locus - STIL) gene was identified because of its involvement in childhood T-ALL. Our studies have revealed a far broader role for SIL. It encodes a cytosolic protein that is important for embryonic development and Hedgehog signaling(10). Physiologically it regulates the entrance to mitosis. It is overexpessed in many types of cancers and its silencing by RNA interference technologies results in cancer cell death in-vitro and in-vivo(11, 12). Our current research aims are to reveal how SIL regulates mitosis and survival and how could it be targeted for cancer therapy.

Research Funding

Research in our center has been supported by the following agencies: Binational Israel-US Foundation (http://www.jewishvirtuallibrary.org/jsource/US-Israel/bsf.html), Children with Leukaemia (UK) (http://www.leukaemia.org/), European Hematology Association (http://www.ehaweb.org/), German Israel Foundation (http://www.gifres.org.il/), Israel Cancer Research Association (http://www.cancer.org.il/), Israel Cancer Research Foundation (http://www.icrfonline.org/), Israel Science Foundation (http://www.isf.org.il/), JNF UK (http://www.jnf.co.uk/), Ministry of Health (http://www.health.gov.il/english/), Ministry of Science (http://www.most.gov.il/), National Institutes of Health (http://grants.nih.gov/grants/guide/), The Wolfson Foundation (http://www.wolfson.org.uk/), Waxman Cancer Research Foundation (http://www.waxmancancer.org/), Hans Altschuler foundation (ZH) and private donations.

International collaborations

Strong international collaboration characterizes our research. Prof Izraeli is the head of the Biology and Diagnosis committee of the iBFM-SG, the largest international cooperative group for the study of childhood leukemia. We collaborate with all iBFM institutions in Europe, with multiple institutions in the USA such as the National Institutes of Health, Northwestern University, Children's Hospital of Michigan, St Jude Children Research Hospital, MD Anderson Cancer Center and more.

Selected publications

1.Izraeli, S., Trisomy 21 tilts the balance. Blood, 2008. 112(12): p. 4361-2.

2.Malinge, S., S. Izraeli, and J.D. Crispino, Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood, 2009. 113(12): p. 2619-28.

3.Rainis, L., D. Bercovich, S. Strehl, A. Teigler-Schlegel, B. Stark, J. Trka, N. Amariglio, A. Biondi, I. Muler, G. Rechavi, H. Kempski, O.A. Haas, and S. Izraeli, Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood, 2003. 102(3): p. 981-6.

4.Rainis, L., T. Toki, J.E. Pimanda, E. Rosenthal, K. Machol, S. Strehl, B. Gottgens, E. Ito, and S. Izraeli, The Proto-Oncogene ERG in Megakaryoblastic Leukemias. Cancer Res, 2005. 65(17): p. 7596-7602.

5.Salek-Ardakani, S., G. Smooha, J. de Boer, N.J. Sebire, M. Morrow, L. Rainis, S. Lee, O. Williams, S. Izraeli, and H.J. Brady, ERG is a megakaryocytic oncogene. Cancer Res, 2009. 69(11): p. 4665-73.

6.Bercovich, D., I. Ganmore, L.M. Scott, G. Wainreb, Y. Birger, A. Elimelech, C. Shochat, G. Cazzaniga, A. Biondi, G. Basso, G. Cario, M. Schrappe, M. Stanulla, S. Strehl, O.A. Haas, G. Mann, V. Binder, A. Borkhardt, H. Kempski, J. Trka, B. Bielorei, S. Avigad, B. Stark, O. Smith, N. Dastugue, J.P. Bourquin, N.B. Tal, A.R. Green, and S. Izraeli, Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet, 2008. 372(9648): p. 1484-92.

7.Ganmore, I., G. Smooha, and S. Izraeli, Constitutional aneuploidy and cancer predisposition. Hum Mol Genet, 2009. 18(R1): p. R84-93.

8.Grinberg-Rashi, H., E. Ofek, M. Perelman, J. Skarda, P. Yaron, M. Hajduch, J. Jacob-Hirsch, N. Amariglio, M. Krupsky, D.A. Simansky, Z. Ram, R. Pfeffer, I. Galernter, D.M. Steinberg, I. Ben-Dov, G. Rechavi, and S. Izraeli, The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain. Clin Cancer Res, 2009. 15(5): p. 1755-61.

9.Cario, G., S. Izraeli, A. Teichert, P. Rhein, J. Skokowa, A. Moricke, M. Zimmermann, A. Schrauder, L. Karawajew, W.D. Ludwig, K. Welte, H.J. Schunemann, B. Schlegelberger, M. Schrappe, and M. Stanulla, High interleukin-15 expression characterizes childhood acute lymphoblastic leukemia with involvement of the CNS. J Clin Oncol, 2007. 25(30): p. 4813-20.

10.Izraeli, S., L.A. Lowe, V.L. Bertness, D.J. Good, D.W. Dorward, I.R. Kirsch, and M.R.

Kuehn, The SIL gene is required for mouse embryonic axial development and left- right specification. Nature, 1999. 399(6737): p. 691-4.

11.Erez, A., A. Castiel, L. Trakhtenbrot, M. Perelman, E. Rosenthal, I. Goldstein, N. Stettner, A. Harmelin, H. Eldar-Finkelman, S. Campaner, I. Kirsch, and S. Izraeli, The SIL gene is essential for mitotic entry and survival of cancer cells. Cancer Res, 2007. 67(9): p. 4022-7.

12.Erez, A., M. Perelman, S.M. Hewitt, G. Cojacaru, I. Goldberg, I. Shahar, P. Yaron, I. Muler, S. Campaner, N. Amariglio, G. Rechavi, I.R. Kirsch, M. Krupsky, N. Kaminski, and S. Izraeli, Sil overexpression in lung cancer characterizes tumors with increased mitotic activity. Oncogene, 2004. 23(31): p. 5371-7.

13.Izraeli, S., L.A. Lowe, V.L. Bertness, S. Campaner, H. Hahn, I.R. Kirsch, and M.R. Kuehn, Genetic evidence that Sil is required for the Sonic Hedgehog response pathway. Genesis, 2001. 31(2): p. 72-7.

14.Hochman, E., A. Castiel, J. Jacob-Hirsch, N. Amariglio, and S. Izraeli, Molecular Pathways Regulating Pro-migratory Effects of Hedgehog Signaling. J Biol Chem, 2006. 281(45): p. 33860-70.

15.Hochman, E., S. Kinston, A. Harmelin, B. Gottgens, and S. Izraeli, The SCL 3' enhancer responds to Hedgehog signaling during hemangioblast specification. Exp Hematol, 2006. 34(12): p. 1643-50.

16.Hertzberg, L., D.R. Betts, S.C. Raimondi, B.W. Schafer, D.A. Notterman, E. Domany, and S. Izraeli, Prediction of chromosomal aneuploidy from gene expression data. Genes Chromosomes Cancer, 2007. 46(1): p. 75-86.

17.Izraeli, S., L. Rainis, L. Hertzberg, G. Smooha, and Y. Birger, Trisomy of chromosome 21 in leukemogenesis. Blood Cells, Molecules, and Diseases, 2007. 39(2): p. 156-159.

18.Erez, A., M. Chaussepied, A. Castiel, T. Colaizzo-Anas, P.D. Aplan, D. Ginsberg, and S. Izraeli, The mitotic checkpoint gene, SIL is regulated by E2F1. Int J Cancer, 2008. 123(7): p. 1721-5.