Thomas Graf (biologist)

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Thomas Graf
ThomasGraf 2015.jpg
Born (1944-09-28) 28 September 1944 (age 76)
Vienna, Austria
Alma mater University of Tübingen
Scientific career
Fields stem cells biology
Institutions European Molecular Biology Laboratory, Albert Einstein College of Medicine, Centre for Genomic Regulation

Thomas Graf (born 28 September 1944) is a biologist at the Centre for Genomic Regulation (CRG) in Barcelona, Spain. He is a pioneer in cell reprogramming, showing that blood cells can be transdifferentiated by transcription factors. [1] [2] He is also known for his early work on oncogenes carried by retroviruses and oncogene cooperation in leukemia formation. [3]

Contents

Research

In the late 70s Graf co-discovered several cell-derived oncogenes acquired by avian retroviruses, designated Mac (later changed into Myc), Erb and Myb. [4] He found that several naturally occurring virus strains have acquired various pairwise combinations of oncogenes and that these cooperate to cause acute leukemia, [5] an early example for the multigenic origin of cancers. He also showed that the transcription factor Myb can reversibly block the differentiation of white blood cells, one of the first demonstrations of induced cell fate changes. [6] In his more recent research he showed that different types of specialized blood cells can be induced to convert into each other by forced transcription factor expression. [7] In 1995 he pioneered this technique permitting the transdifferentiation of white blood cells into red blood cell precursors and vice versa induced by Gata1 [8] and PU.1, respectively. Later (2004) he managed to convert B lymphocytes into functional macrophages, using C/EBPa as a driver. [9] Using the same approach he was also first to induce a conversion of more distantly related cells, namely that of non-blood cells into macrophages. [10] Finally, he found that forced C/EBPa expression in malignant lymphocyte precursors leads to the formation of macrophages and loss of tumorigenicity, [11] suggesting transdifferentiation as an alternative avenue for therapeutic interventions.

Awards

Related Research Articles

Oncogene Gene that has the potential to cause cancer

An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

Transdifferentiation, also known as lineage reprogramming, is an artificial process in which one mature somatic cell is transformed into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type. It is a type of metaplasia, which includes all cell fate switches, including the interconversion of stem cells. Current uses of transdifferentiation include disease modeling and drug discovery and in the future may include gene therapy and regenerative medicine. The term 'transdifferentiation' was originally coined by Selman and Kafatos in 1974 to describe a change in cell properties as cuticle producing cells became salt-secreting cells in silk moths undergoing metamorphosis.

Adult T-cell leukemia/lymphoma Human disease

Adult T-cell leukemia/lymphoma is a rare cancer of the immune system's T-cells caused by human T cell leukemia/lymphotropic virus type 1 (HTLV-1). All ATL cells contain integrated HTLV-1 provirus further supporting that causal role of the virus in the cause of the neoplasm. A small amount of HTLV-1 individuals progress to develop ATL with a long latency period between infection and ATL development. ATL is categorized into 4 subtypes: acute, smoldering, lymphoma-type, chronic. Acute and Lymphoma-type are known to particularity be aggressive with poorer prognosis.

Interleukin 3

Interleukin 3 (IL-3) is a protein that in humans is encoded by the IL3 gene localized on chromosome 5q31.1. Sometimes also called colony-stimulating factor, multi-CSF, mast cell growth factor, MULTI-CSF, MCGF; MGC79398, MGC79399: the protein contains 152 amino acids and its molecular weight is 17 kDa. IL-3 is produced as a monomer by activated T cells, monocytes/macrophages and stroma cells. The major function of IL-3 cytokine is to regulate the concentrations of various blood-cell types. It induces proliferation and differentiation in both early pluripotent stem cells and committed progenitors. It also has many more specific effects like the regeneration of platelets and potentially aids in early antibody isotype switching.

ABL (gene) Human protein-coding gene on chromosome 9

Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene, which was initially isolated from the Abelson murine leukemia virus.

Juvenile myelomonocytic leukemia (JMML) is a serious chronic leukemia that affects children mostly aged 4 and younger. The name JMML now encompasses all diagnoses formerly referred to as juvenile chronic myeloid leukemia (JCML), chronic myelomonocytic leukemia of infancy, and infantile monosomy 7 syndrome. The average age of patients at diagnosis is 2 years old. The World Health Organization has included JMML in the category of myelodysplastic and myeloproliferative disorders.

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2, Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

MYB (gene)

Myb genes are part of a large gene family of transcription factors found in animals and plants. In humans, it includes Myb proto-oncogene like 1 and Myb-related protein B in addition to MYB proper. Members of the extended SANT/Myb family also include the SANT domain and other similar all-helical homeobox-like domains.

HOXA9

Homeobox protein Hox-A9 is a protein that in humans is encoded by the HOXA9 gene.

GATA2

GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming, lympathic system-forming, and other tissue-forming stem cells. GATA2 is encoded by the GATA2 gene, a gene which often suffers germline and somatic mutations which lead to a wide range of familial and sporadic diseases, respectively. The gene and its product are targets for the treatment of these diseases.

Thrombopoietin receptor

The thrombopoietin receptor also known as the myeloproliferative leukemia protein or CD110 is a protein that in humans is encoded by the MPL oncogene.

HOXB6

Homeobox protein Hox-B6 is a protein that in humans is encoded by the HOXB6 gene.

<i>MAFB</i> (gene)

Transcription factor MafB also known as V-maf musculoaponeurotic fibrosarcoma oncogene homolog B is a protein that in humans is encoded by the MAFB gene. This gene maps to chromosome 20q11.2-q13.1, consists of a single exon and spans around 3 kb.

MXD1

MAD protein is a protein that in humans is encoded by the MXD1 gene.

IL3RA human gene

Interleukin 3 receptor, alpha (IL3RA), also known as CD123, is a human gene.

Cell potency Ability of a cell to differentiate into other cell types

Cell potency is a cell's ability to differentiate into other cell types. The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell, which like a continuum, begins with totipotency to designate a cell with the most differentiation potential, pluripotency, multipotency, oligopotency, and finally unipotency.

Martin Zenke

Martin Zenke born August 7, 1953 in Korbach is a German biochemist, cell biologist, Professor for Cell Biology and scientist, who is conducting research on stem cells and biomedical engineering.

A list of examples of transdifferentiation:

A list of examples of in vivo transdifferentiation through transfection:

Induced stem cells (iSC) are stem cells derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming. They are classified as either totipotent (iTC), pluripotent (iPSC) or progenitor or unipotent – (iUSC) according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells.

References

  1. ↑ Graf, Thomas (2011-12-02). "Historical Origins of Transdifferentiation and Reprogramming". Cell Stem Cell. 9 (6): 504–516. doi: 10.1016/j.stem.2011.11.012 . ISSN   1934-5909. PMID   22136926.
  2. ↑ Baker, Monya (2008-10-23). "Thomas Graf: Cellular identity and transdifferentiation". Nature Reports Stem Cells. doi: 10.1038/stemcells.2008.140 .
  3. ↑ Metz, T.; Graf, T. (1991-07-12). "Fusion of the nuclear oncoproteins v-Myb and v-Ets is required for the leukemogenicity of E26 virus". Cell. 66 (1): 95–105. doi:10.1016/0092-8674(91)90142-L. ISSN   0092-8674. PMID   2070421.
  4. ↑ Roussel, M.; Saule, S.; Lagrou, C.; Rommens, C.; Beug, H.; Graf, T.; Stehelin, D. (1979-10-11). "Three new types of viral oncogene of cellular origin specific for haematopoietic cell transformation". Nature. 281 (5731): 452–455. doi:10.1038/281452a0. PMID   226888.
  5. ↑ Graf, Thomas; Beug, Hartmut (1983-08-01). "Role of the v-erbA and v-erbB oncogenes of avian erythroblastosis virus in erythroid cell transformation". Cell. 34 (1): 7–9. doi:10.1016/0092-8674(83)90130-7. ISSN   0092-8674. PMID   6309413.
  6. ↑ Beug, H.; Blundell, P. A.; Graf, T. (May 1987). "Reversibility of differentiation and proliferative capacity in avian myelomonocytic cells transformed by tsE26 leukemia virus". Genes & Development. 1 (3): 277–286. doi: 10.1101/gad.1.3.277 . ISSN   0890-9369. PMID   2824281.
  7. ↑ Graf, Thomas; Enver, Tariq (2009). "Forcing cells to change lineages". Nature. 462 (7273): 587–594. doi:10.1038/nature08533. PMID   19956253.
  8. ↑ Kulessa, H.; Frampton, J.; Graf, T. (1995-05-15). "GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts". Genes & Development. 9 (10): 1250–1262. doi: 10.1101/gad.9.10.1250 . ISSN   0890-9369. PMID   7758949.
  9. ↑ Xie, Huafeng; Ye, Min; Feng, Ru; Graf, Thomas (2004-05-28). "Stepwise Reprogramming of B Cells into Macrophages". Cell. 117 (5): 663–676. doi: 10.1016/S0092-8674(04)00419-2 . ISSN   0092-8674. PMID   15163413.
  10. ↑ Feng, R.; Desbordes, S. C.; Xie, H.; Tillo, E. S.; Pixley, F.; Stanley, E. R.; Graf, T. (2008). "PU.1 and C/EBP / convert fibroblasts into macrophage-like cells". Proceedings of the National Academy of Sciences. 105 (16): 6057–6062. doi:10.1073/pnas.0711961105. PMC   2327209 . PMID   18424555.
  11. ↑ Rapino, Francesca; Robles, Eloy F.; Richter-Larrea, Jose A.; Kallin, Eric M.; Martinez-Climent, Jose A.; Graf, Thomas (2013-04-25). "C/EBPα Induces Highly Efficient Macrophage Transdifferentiation of B Lymphoma and Leukemia Cell Lines and Impairs Their Tumorigenicity". Cell Reports. 3 (4): 1153–1163. doi: 10.1016/j.celrep.2013.03.003 . ISSN   2211-1247. PMID   23545498.
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