Plzf pushes stem cells

© 2004 Nature Publishing Group http://www.nature.com/naturegenetics NEWS AND VIEWS analyzed (five of seven) showed additional chromosomal abnormalities, with amplification of the chromosome 15 region harboring Myc observed in four of seven cases. Normal hematopoiesis requires the precise regulation of multiple pathways whose activities fluctuate during proliferation and differentiation. Individual genes in these pathways are like ‘on-off’ switches that dictate the level of activity in a given pathway, and investigators hypothesize that leukemogenesis results from an absolute disruption in one or more of these switches. Such errors are usually associated with activating mutations that turn the switch on at the wrong time (RAS, FLT3) or with the creation of new chimeric proteins (Bcr-Abl, PML-RARα, RUNX1-CBFA2T1) that perturb the regulatory system. In the 1990s, however, numerous studies showed that loss of heterozygosity of some tumor suppressor genes can promote malignant transformation, suggesting that a haploinsufficient dosage effect may have a role in tumorigenesis10,11. Rosenbauer et al. expanded on this concept by showing that a dosage effect for PU.1 exists between haploinsufficient and null expression states. These results suggest that investigators must look beyond the concept of genes merely acting as on-off switches and begin considering how small fluctuations in activity impact the biology of the cell. Looking to the future, research will need to more accurately define the interactions between genes and molecular pathways to develop a clearer picture of what constitutes the ‘normal’ and ‘abnormal’ regulatory processes of cells. These investigations will necessitate the development of new quantitative approaches and improvements in existing technologies such as DNA microarrays and proteomics. The elaborate networks controlling cellular functions have multiple checks and balances. For example, RAS mutations, which are constitutively active, upregulate p53 activity, resulting in apoptosis if the p53 tumor suppressor pathway remains functional12. Therefore, it is not surprising that multiple genetic ‘hits’ are necessary to promote leukemogenesis. Recently, investigators found that mutations in FLT3 can cooperate with PML-RARα rearrangements to promote rapid development of a leukemia-like disease in a transgenic mice, whereas either genetic abnormality alone induces primarily a myeloproliferative-like syndrome13. These results, combined with those of Rosenbauer et al., argue that initial genetic events promote an undifferentiated or preleukemic state that makes cells susceptible to additional genetic damage. The phenotype of this preleukemic state is similar to that found in myeloproliferative diseases, in which there is an expansion of the primitive hematopoietic cell compartment. Additional genetic abnormalities, like FLT3 mutations or overexpression of c-Myc, push these cells into an aggressive leukemic phenotype. These findings are consistent with the multiple-hit theory of carcinogenesis, first proposed for solid tumors such as colon cancer14. The primary clinical implications from these findings are that cells in a preleukemic state retain some normal regulatory pathways. Therefore, these cells should be much more susceptible, in theory, to targeted therapies that induce preleukemic cells into a normal pathway of differentiation, and perhaps apoptosis. Once cells have evolved to a leukemic state, many of these regulatory processes have been by-passed, making targeted approaches less likely to succeed. This concept has been clearly validated in chronic myelogenous leukemia, in which the small molecular inhibitor Imatinib is effective in treating chronic myelogenous leukemia in chronic phase but has limited efficacy once the disease has progressed to blast phase, a more aggressive and overtly leukemic state15. 1. Klemsz, M.J., McKercher, S.R., Celada, A., Van Beveren, C. & Maki, R.A. Cell 61, 113–124 (1990). 2. DeKoter, R.P., Walsh, J.C. & Singh, H. EMBO J. 17, 4456–4468 (1998). 3. Zheng, R. et al. Blood 103, 1883–1890 (2004). 4. Vangala, R.K. et al. Blood 101, 270–277 (2003). 5. Rosenbauer, F. et al. Nat. Genet. 36, 624–630 (2004). 6. Li, Y. et al. Blood 98, 2958–2965 (2001). 7. Scott, E.W. et al. Immunity 6, 437–447 (1997). 8. Scott, E.W., Simon, M.C., Anastasi, J. & Singh, H. Science 265, 1573–1577 (1994). 9. Iwama, A. et al. Nucleic Acids Res. 26, 3034–3043 (1998). 10. Fero, M.L., Randel, E., Gurley, K.E., Roberts, J.M. & Kemp, C.J. Nature 396, 177–180 (1998). 11. Venkatachalam, S. et al. EMBO J. 17, 4657–4667 (1998). 12. Palmero, I., Pantoja, C. & Serrano, M. Nature 395, 125–126 (1998). 13. Kelly, L.M. et al. Proc. Natl. Acad. Sci. USA 99, 8283–8288 (2002). 14. Vogelstein, B. et al. N. Engl. J. Med. 319, 525–532 (1988). 15. Sawyers, C.L. et al. Blood 99, 3530–3539 (2002). Plzf pushes stem cells Noora Kotaja & Paolo Sassone-Corsi The molecular mechanisms that regulate the balance between differentiation and self-renewal in spermatogonial stem cells are elusive. Two studies now show that the transcriptional repressor Plzf is an essential regulator of spermatogonial stem cell maintenance. Among cell lineages, germ cells are unique in that they can generate a new organism. In males, germline stem cells provide a source of undifferentiated cells that allow spermatogenesis to proceed throughout the period of sexual maturity. Cells committed to differentiate enter the meiotic Noora Kotaja and Paolo Sassone-Corsi are at the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France. e-mail: pathway, which comprises a unique program of gene expression and chromatin remodeling1. To maintain the stem cell pool, however, some germ cells must remain undifferentiated and proliferate through cyclic mitotic divisions. How does each spermatogonial stem cell decide whether to proliferate or differentiate? The molecular mechanisms controlling this delicate balance are largely unknown. New studies by F. William Buaas and colleagues and José Costoya and colleagues published NATURE GENETICS VOLUME 36 | NUMBER 6 | JUNE 2004 in this issue2,3 provide clues to the mechanisms required for self-renewal of spermatogonial stem cells by showing that the transcriptional repressor Plzf is required for stem cell maintenance. An epigenetic connection Plzf (promyelocytic leukemia zinc-finger) belongs to the POK (POZ and Krüppel) family of transcriptional repressors. In addition to nine Krüppel-type sequence-specific zinc fingers, Plzf contains a conserved POZ 551 NEWS AND VIEWS cAMP FSH Hypothalamic pituitary axis Sertoli cell Steel locus GDNF FSH receptor Proteolytic cleavage SCF precursor GDNF © 2004 Nature Publishing Group http://www.nature.com/naturegenetics Differentiation signals ? Stem cell self-renewal Ret SCF c-Kit ? PI3K Apoptosis survival Akt-PKB Bcl-X-Bax ? HDAC PLZF X Spermatogonia Figure 1 Some known signaling cascad (...truncated)