Apoptosis; Alternative splicing; Chemoresistance; PU.1; Acute Myeloid Leukemia; TRAIL
Humbert Magali, Morán María, Cruz-Ojeda Patricia de la, Muntané Jordi, Wiedmer Tabea, Apostolova Nadezda, McKenna Sharon L., Velasco G, Balduini Walter, Eckhart Leopold, Janji Bassam, Sampaio-Marques Belém, P Ludovico, Žerovnik Eva, Langer Rupert, Perren Aurel, Engedal Nikolai, Tschan Mario P. (2020), Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot, in Biology
Humbert Magali, Seiler Kristina, Mosimann Severin, Rentsch Vreni, McKenna Sharon L, Tschan Mario P (2020), Autophagy-mediated degradation of Fatty Acid Synthase (FASN) facilitates ATRA-induced granulocytic differentiation of acute myeloid leukemia (AML) cells, in BioRxiv
Jin Jing, Britschgi Adrian, Schläfli Anna M., Humbert Magali, Shan-Krauer Deborah, Batliner Jasmin, Federzoni Elena A., Ernst Marion, Torbett Bruce E., Yousefi Shida, Simon Hans-Uwe, Tschan Mario P. (2018), Low Autophagy (ATG) Gene Expression Is Associated with an Immature AML Blast Cell Phenotype and Can Be Restored during AML Differentiation Therapy, in Oxidative Medicine and Cellular Longevity
, 2018, 1-16.
Schläfli Anna M, Isakson Pauline, Garattini E, Simonsen Anne, Tschan Mario P (2017), The autophagy scaffold protein ALFY is critical for the granulocytic differentiation of AML cells., in Scientific reports
, 7(1), 12980-12980.
Haimovici Aladin, Humbert Magali, Federzoni Elena A, Shan-Krauer Deborah, Brunner Thomas, Frese Steffen, Kaufmann Thomas, Torbett Bruce E, Tschan Mario P (2017), PU.1 supports TRAIL-induced cell death by inhibiting NF-κB-mediated cell survival and inducing DR5 expression, in Cell Death & Differentiation
, 24(5), 866-877.
, Inhibition of UBE2L6 attenuates ISGylation and impedes ATRA‐induced differentiation of leukemic cells, in Molecular Oncology
The ETS-transcription factor PU.1 is needed throughout hematopoietic differentiation particularly by orchestrating terminal differentiation of macrophages, neutrophils, B-cells and Th9 cells. The role of PU.1 in myeloid differentiation and its regulation have been thoroughly investigated and many genes directly involved in myeloid development and function are transcriptional targets of PU.1. Importantly, low but not absent PU.1 expression can lead to the transformation of myeloid progenitor cells to acute myeloid leukemia (AML). Thus, PU.1 is regarded as a tumor suppressor in AML, a disease that is characterized by an accumulation of immature blast cells with increased cell survival. Much less information is available on PU.1’s function in cell death or cell cycle regulation. Comprehensive functional studies analyzing the role of PU.1 during cell death responses of AML cells to cancer therapies are missing. Our preliminary data describe a new tumor suppressor function for PU.1 by supporting TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in AML cells. Our data indicate that PU.1 represses the NF-?B survival pathway, and thus the induction of anti-apoptotic genes such as cFLIP, Bcl-2 or Mcl-1. Furthermore, blocking PU.1 expression causes a shift in cFLIP expression towards the anti-apoptotic splice variant cFLIPshort. Altogether, these results indicate a new facet of PU.1's tumor suppressor function during anti-leukemic therapy and low PU.1 levels may contribute to resistance towards TRAIL treatment. Moreover, inhibiting PU.1 also attenuates AML cell toxicity caused by anthracycline-based therapies. In my opinion, further studies to decipher mechanisms how PU.1 affects cell death and how PU.1 protein stability is regulated during cancer therapy warrants further investigations. Findings from this project hold potential for improved therapeutic strategies in mainly AML treatment and a better understanding of how PU.1 keeps neoplastic transformations in check. I propose to investigate in more detail how PU.1 regulates responses to cytotoxic particularly death receptor mediated therapies I suggest to address the following objectives: I. PU.1 mechanisms in response to cytotoxic therapy. I propose, (a) to validate our 2D cell culture findings in 3D in vitro and in vivo, (b) to further characterize PU.1’s cell death function in regard of TRAIL receptor regulation, (c) to validate possible apoptotic functions of PU.1 in additional hematopoietic neoplasms, (d) to investigate PU.1’s role in epigenetic regulation of cell death-associated genes. II. I propose, (a) to initially investigate if blocking major cellular degradation processes (e.g. caspases, necroptosis, proteasome, autophagy) affect PU.1 protein expression, and (b) to characterize the PU.1 protein interactome during cytotoxic treatment and to inhibit/activate newly identified proteins involved in PU.1 protein stability for novel therapeutic options in cytotoxic therapies.III. PU.1 and alternative splicing of cFLIP. I propose, (a) to analyze the function of cFLIP in resistance towards TRAIL treatment and chemotherapy, (b) to test if PU.1 associates with the cFLIP promoter region to promote specific use of splice sites, and (c) to investigate if PU.1 transcriptionally regulates posttranslational modifiers of cFLIP.The proposed studies will help to unravel novel functions of PU.1 in cell death responses to cancer therapies and may further elucidate its role in suppressing leukemia by targeting anti-apoptotic proteins. Identifying factors that regulate PU.1 protein stability may provide novel targets to be used in combination with current cytotoxic therapies.