Leo Sachs

The Otto Meyerhof Professor of Molecular Biology

Room: 226

Building: Arthur and Rochelle Belfer Building for Biomedical Research

Tel: 972-8-934-4068

Fax: 972-8-934-4108

e-mail: leo.sachs@weizmann.ac.il

 





Control of Development of Normal and Malignant Stem Cells: From Basic Studies on Blood Cells to New Therapies

Normal bone marrow stem cells can give rise to the different types of blood cells and to other cell types such as neuronal, muscle and epithelial cells. This is an excellent system to study regulation of the developmental potentials of stem cells and the use of stem cells from adults for therapy. Our establishment of a cell culture system for the clonal development of hematopoietic stem cells made it possible to discover the proteins that regulate cell viability, multiplication and differentiation of different hematopoietic cell lineages and the molecular basis of normal and abnormal blood cell development. The first proteins discovered in this way are cytokines now called colony stimulating factors (CSFs) and they also now include various other cytokines. There is a network of cytokine interactions, which has positive regulators such as a CSFs and interleukins (ILs) and negative regulators such as transforming growth factor b (TGFb) and tumor necrosis factor (TNF) (Fig. 1). This network includes a cytokine cascade that ensures effective coupling of cell multiplication and differentiation.

Fig. 1 Network of hematopoietic cytokines (Sachs, 1995)

Malignancy can be suppressed in certain types of leukemic stem cells by inducing differentiation with cytokines that regulate normal hematopoiesis or with other compounds that use alternative differentiation pathways. This created the basis for the clinical use of differentiation therapy. The suppression of malignancy by inducing differentiation can bypass genetic abnormalities that give rise to malignancy and showed that cancer stem cells, which are genetically abnormal, can be epigenetically reprogrammed (Fig. 2). Epigenetics can thus win over genetics.

Fig. 2 Epigenetic suppression of malignancy by inducing differentiation. Malignant cells are genetically abnormal. The malignant phenotype can be epigenetically reprogrammed to a non-malignant phenotype by inducing differentiation. (Lotem and Sachs, 2002a)

In addition to inducing cell multiplication and differentiation, different cytokines including CSFs and ILs suppress programmed cell death (apoptosis). The same cytokines suppress apoptosis in normal and leukemic cells, including apoptosis induced by irradiation and cytotoxic cancer chemotherapeutic compounds. An excess of cytokines can increase leukemic cell resistance to cytotoxic therapy. The tumor suppressor gene wild-type p53 can induce apoptosis and oncogenic p53 mutants can suppress apoptosis. There is a network of apoptosis inducing and suppressing genes. Apoptosis induced by wild-type p53 was suppressed by cytokines and various other agents such as antioxidants, calcium mobilizing compounds, coumarin and flavone inhibitors of NAD(P)H: quinone oxidoreductase 1 (NQO1), and some other inhibitors. Dissection of the pathways of apoptosis has shown that there are different pathways of apoptosis that were suppressed by cytokines and by different inhibitors. The use of DNA microarrays and a cluster analysis of expressed genes (Fig. 3) has shown that a cytokine can suppress wild type p53 induced apoptosis without affecting expression of p53 regulated genes.

Fig. 3 Cluster analysis of up-regulated and down-regulated genes by wild type p53 in the absence or presence of the cytokine IL-6. a, dendrogram and b, expression matrix in which colors represent induction (red) or suppression (blue) (Lotem et al., 2003)

DNA microarray studies with murine and human leukemias have shown that cancers over express genes that are specific to a variety of normal tissues including normal tissues other than those from which the tumors were derived.
A hematopoietic cytokine such as granulocyte CSF is now used clinically to correct defects in hematopoiesis, including repair of irradiation and chemotherapy associated suppression of normal hematopoiesis in cancer patients, repair of normal granulocyte development in patients with infantile genetic agranulocytosis, and to induce migration of stem cells from the bone marrow to peripheral blood for stem cell transplantation. Treatments that decrease the level of apoptosis suppressing cytokines and downregulate expression of apoptosis suppressing genes in cancer cells could improve cytotoxic cancer therapy. The basic studies on normal bone marrow and leukemic stem cells have provided new approaches to therapy, including the therapeutic use of stem cells from adults.

Keywords: Apoptosis, bone marrow, cancer, colony stimulating factors, cytokines, differentiation, epigenetics, hematopoiesis, interleukins, leukemia, microarrays, networks, p53, normal and malignant stem cells, therapy

 

Some Recent References

Sachs, L. (1995) The adventures of a biologist: Prenatal diagnosis, hematopoiesis, leukemia, carcinogenesis and tumor suppression. Foundations in Cancer Research. Adv. Cancer Res. 66: 1-40.

Lotem, J., and Sachs, L. (1995) Regulation of bcl-2, bcl-XL and bax in the control of apoptosis by hematopoietic cytokines and dexamethasone. Cell Growth Differ., 6:647-653.

Peled-Kamar, M., Lotem, J., Okon, E., Sachs, L., and Groner, Y. (1995) Thymic abnormalities and enhanced apoptosis of thymocytes and bone marrow cells in transgenic mice overexpressing Cu/Zn-superoxide dismutase: implications for Down syndrome. EMBO J., 14:4985-4993.

Lotem, J., and Sachs, L. (1995) A mutant p53 antagonizes the deregulated c-myc mediated enhancement of apoptosis and decrease in leukemogenicity. Proc. Natl. Acad. Sci. USA, 92:9672-9676. PDF Version

Sachs, L. (1996) The control of hematopoiesis and leukemia: From basic biology to the clinic. Proc. Natl. Acad. Sci. USA, 93:4742-4749. PDF Version

Lotem, J., Peled-Kamar, M., Groner, Y., and Sachs, L. (1996) Cellular oxidative stress and the control of apoptosis by wild-type p53, cytotoxic compounds and cytokines. Proc. Natl. Acad. Sci. USA, 93:9166-9171. PDF Version

Kaplinsky, C., Lotem, J. and Sachs, L. (1996) Protection of human myeloid leukemic cells against doxorubicin-induced apoptosis by granulocyte-macrophage colony-stimulating factor and interleukin 3. Leukemia, 10:460-465.

Lotem, J., and Sachs, L. (1997) Cytokine suppression of protease activation in wild-type p53-dependent and p53-independent apoptosis. Proc. Natl. Acad. Sci. USA, 94:9349-9353. PDF Version

Lotem, J., and Sachs, L. (1998) Different mechanisms for suppression of apoptosis by cytokines and calcium mobilizing compounds. Proc. Natl. Acad. Sci. USA, 95:4601-4606. PDF Version

Lotem, J. and Sachs, L. (1999) Cytokines as suppressors of apoptosis. Apoptosis, 4:187-196. PDF Version

Lotem, J., Kama, R. and Sachs, L. (1999) Suppression or induction of apoptosis by opposing pathways downstream from calcium-activated calcineurin. Proc. Natl. Acad. Sci. USA, 96:12016-12020. PDF Version

Asher, G., Lotem, J., Cohen, B., Sachs, L. and Shaul, Y. (2001) Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxireductase 1. Proc. Natl. Acad. Sci. USA, 98:1188-1193. PDF Version

Asher, G., Lotem, J., Kama, R., Sachs, L. and Shaul, Y. (2002) NQO1 stabilizes p53 through a distinct pathway. Proc. Natl. Acad. Sci. USA, 99:3099-3104. PDF Version

Yuan, X.-M., Li, W., Dalen H., Lotem, J., Kama, R., Sachs, L. and Brunk, U.T. (2002) Lysosomal destabilization in p53-induced apoptosis. Proc. Natl. Acad. Sci. USA, 99:6286-6291. PDF Version

Lotem, J. and Sachs, L. (2002a) Epigenetics wins over genetics. Induction of differentiation in tumor cells. Sem. Cancer Biol. 12:330-346. PDF Version

Lotem, J. and Sachs, L. (2002) Cytokine control of developmental programs in normal hematopoiesis and leukemia. Oncogene, 21:3284-3294. PDF Version

Asher, G., Lotem, J., Sachs, L., Kahana, C. and Shaul, Y. (2002) Mdm-2 and ubiquitin- independent p53 proteosomal degradation regulated by NQO1. Proc. Natl. Acad. Sci. USA, 99:13125-13130. PDF Version

Lotem, J., Gal, H., Kama, R., Amariglio, N., Rehavi, G., Domany, E., Sachs, L. and Givol, D. (2003) Inhibition of p53-induced apoptosis without affecting expression of p53-regulated genes. Proc. Natl. Acad. Sci. USA, 100:6718-6723. PDF Version

Asher, G. Lotem, J., Tsvetkov, P., Reiss, V., Sachs, L. and Shaul, Y. (2003) p53 hot spot mutants are resistant to ubiquitin-independent degradation by increased binding to NAD(P)H: quinone oxireductase 1. Proc. Natl. Acad. Sci. USA, 100: 15065-15070. PDF Version

Lotem, J., Benjamin, H., Netanely, D., Domany, E., and Sachs, L. (2004) Induction in myeloid leukemic cells of genes that are expressed in different normal tissues, Proc. Natl. Acad. Sci. USA, 101: 16022-16027.

Lotem, J., Netanely, D., Domany, E., and Sachs, L. (2005) Human cancers overexpress genes that are specific to a variety of normal human tissues. Proc. Natl. Acad. Sci. USA, 102: 18556-18561

Tsvetkov, P., Asher, G., Reiss, V., Shaul, Y., Sachs, L., and Lotem, J. (2005) Inhibition of NAD(P)H:quinone oxidoreductase 1 activity and induction of p53 degradation by the natural phenolic compound curcumin. Proc. Natl. Acad. Sci. USA 103: 5535-5540.

Lotem, J. and Sachs, L. (2006) Epigenetics and the plasticity of differentiation in normal and cancer stem cell. Oncogene 25: 7663-7672.

Honors: 1965: Member, European Molecular Biology Organisation; 1972: Israel Prize for Natural Sciences; Harvey Lecture, Rockefeller University, New York; Fogarty Scholar, U.S.A. National Institutes of Health, Bethesda; 1975: Member, Israel Academy of Sciences and Humanities; 1977; Rothschild Prize in the Biological Sciences; 1980: Wolf Prize in Medicine; 1983: Bristol-Myers Award for Distinguished Achievement in Cancer Research, New York; 1985: Doctor Honoris Causa, Bordeaux University, France; 1986: The Royal Society Wellcome Foundation Prize, London; 1989: Alfred P. Sloan Prize, General Motors Cancer Research Foundation, New York; 1995: Foreign Associate, USA National Academy of Sciences; 1997: Fellow of the Royal Society, London; Warren Alpert Foundation Prize, Harvard Medical School, Boston; Doctor of Medicine Honoris Causa, Lund University, Sweden; 1998: Foreign Member, Academia Europaea; 1999: Honorary Fellow, University of Wales, Bangor; 2000: Ham-Wasserman Lecture, American Society of Hematology, San Francisco; 2001: Honorary Life Membership Award, International Cytokine Society; 2002: Emet Prize for Life Sciences, Medicine and Genetics.

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Department of Molecular Genetics
Weizmann Institute of Science
Rehovot
Israel

Tel: 972-8-934-3970
Fax: 972-8-934-4108

e-mail: Karni.Hertz@weizmann.ac.il

Last Updated: 10 August 2008