Tschan Mario P, Federzoni Elena A, Haimovici Aladin, Britschgi Christian, Moser Bettina A, Jin Jing, Reddy Venkateshwar A, Sheeter Dennis A, Fischer Kimberlee M, Sun Peiqing, Torbett Bruce E (2015), Human DMTF1β antagonizes DMTF1α regulation of the p14(ARF) tumor suppressor and promotes cellular proliferation., in Biochimica et biophysica acta
, 1849(9), 1198-1208.
Federzoni Elena A, Gloor Severin, Jin Jing, Shan-Krauer Deborah, Fey Martin F, Torbett Bruce E, Tschan Mario P (2015), Linking the SUMO protease SENP5 to neutrophil differentiation of AML cells., in Leukemia research reports
, 4(1), 32-5.
Brockmann A, Bluwstein A, Kögel A, May S, Marx A, Tschan M P, Brunner T (2015), Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation., in Cell death & disease
, 6, 1778-1778.
Federzoni EA, Humbert M, Torbett BE, Behre G, Fey MF, Tschan MP (2014), CEBPA-dependent HK3 and KLF5 expression in primary AML and during AML differentiation., in Scientific Reports
Haimovici Aladin, Brigger Daniel, Torbett Bruce E, Fey Martin F, Tschan Mario P (2014), Induction of the autophagy-associated gene MAP1S via PU.1 supports APL differentiation., in Leukemia research
, 38(9), 1041-7.
Helbling Melina, Lukesch Anne, Haimovici Aladin, Karamitopoulou Eva, Berger Martin D, Hädrich Marion, Mallaev Makhmud, Schnüriger Beat, Koelzer Viktor H, Dawson Heather, Borner Markus, Langer Rupert, Rosenberg Robert, Nitsche Ulrich, Inderbitzin Daniel, Lugli Alessandro, Tschan Mario, Zlobec Inti (2014), Investigation of IL-23 (p19, p40) and IL-23R identifies nuclear expression of IL-23 p19 as a favorable prognostic factor in colorectal cancer: a retrospective multicenter study of 675 patients., in Oncotarget
, 5(13), 4671-82.
Trocoli A., Bensadoun P., Richard E., Labrunie G., Merhi F., Schlaefli A. M., Brigger D., Souquere S., Pierron G., Pasquet J-M, Soubeyran P., Reiffers J., Segal-Bendirdjian E., Tschan M. P., Djavaheri-Mergny M. (2014), p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells, in CELL DEATH AND DIFFERENTIATION
, 21(12), 1852-1861.
Ségal-Bendirdjian E (2014), Pro-survival role of p62 during granulocytic differentiation of acute myeloid leukemia cells., in Molecular & Cellular Oncology
Brigger D, Proikas-Cezanne T, Tschan M P (2014), WIPI-dependent autophagy during neutrophil differentiation of NB4 acute promyelocytic leukemia cells., in Cell death & disease
, 5, 1315-1315.
Delgado TJ, Adrian J, Kopp K, Scholz P, Tschan MP, Kuespert K, Hauck CR, The granulocyte orphan receptor CEACAM4 is able to trigger phagocytosis of bacteria., in J Leukoc Biol
PU.1-regulated apoptosis and autophagy pathways in neutrophil differentiation of normal and leukemic myeloid precursor cells1. Summary of the research planAcute myeloid leukemia (AML) is characterized by the accumulation of myeloid precursor cells that are blocked in their differentiation and show increased cell survival. A subgroup of AML patients, acute promyelocytic leukemia (APL) patients, is successfully treated with a combination of differentiation therapy using pharmacological doses of all-trans retinoic acid (ATRA) and chemotherapy. ATRA treatment resolves the differentiation block in APL cells via the proteasomal degradation of PML-RARA, the oncogenic fusion protein found in APL. Recently, two studies identified a function for autophagy in PML-RARA degradation induced by ATRA. Autophagy is a proteolytic self-degradation process characterized by the formation of double-membraned vesicles, autophagosomes, which engulf cytoplasmic contents. The autophagosomes then fuse with lysosomes allowing the degradation of its contents. Interestingly, inhibiting the autophagy machinery by knocking down autophagy-related genes (ATGs) also attenuates neutrophil differentiation of non-APL cells. An important PML-RARA-repressed gene is the myeloid master regulator PU.1. In normal hematopoiesis, studies in PU.1 null mice revealed that PU.1 is absolutely required for the development of several myeloid lineages as well as B lymphocytes. In these lineages PU.1 regulates the expression of many genes required for terminally differentiated cells to function. Importantly, PU.1 is not only repressed in APL but generally in AML. For example, direct repression of PU.1 transcription was seen by AML-ETO in AML with the translocation t(8;21) or by FLT-3 mutations. Thus, PU.1 repression is a common feature of most AML samples. The overall importance of PU.1 in myelopoiesis is further reflected by the fact that re-expression of PU.1 not only in APL but also in other AML subtypes can restore differentiation of the leukemic blasts. On the other hand, we and others described a new role for PU.1 in cell survival and apoptosis of neutrophils and other hematopoietic cells by directly regulating, depending on the cellular background, anti- or pro-apoptotic genes. For example, PU.1 regulates the pro-apoptotic gene TRAIL in cell death responses of myeloma cells. We showed that the Bcl2 family member BCL2A1 and the glycolytic enzyme hexokinase 3 (HK3) are novel PU.1 transcriptional targets that are involved in neutrophil cell survival. In summary, molecular pathways of normal myeloid cell differentiation, as well as the mechanisms by which oncogenes disrupt this process, remain poorly understood. Focusing on the myeloid master regulator PU.1 and its novel role in cell death and survival, I propose to address the following specific aims: I. PU.1 and apoptosis. I propose, (a) to analyze PU.1-mediated cell death mechanism in normal and leukemic myeloid cells, (b) to validate and characterize novel PU.1 transcriptional targets associated with cell death (CORO1A, c-FLIP, DAPK2) in myeloid cell survival, and (c) to further characterize the function of the novel PU.1 target hexokinase 3 in cell survival and metabolism of neutrophil cells. II. PU.1 and autophagy. I propose, (a) to investigate if PU.1 contributes to myeloid autophagy and (b) to characterize novel PU.1 transcriptional targets associated with autophagy (WIPI1, MAP1S) in myeloid differentiation and cell death responses.The proposed studies will shed further light on the mechanisms on how PU.1 impacts on cell survival and cell death of normal and leukemic myeloid cells via directly activating genes involved in apoptosis and autophagy. Understanding these processes will help to improve differentiation as well as cytotoxic therapies in the treatment of AML and will contribute to a better understanding of neutrophil cell death.