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Jerome Tamburini

Bio: Jerome Tamburini is an academic researcher from University of Paris. The author has contributed to research in topics: Myeloid leukemia & PI3K/AKT/mTOR pathway. The author has an hindex of 38, co-authored 135 publications receiving 9567 citations. Previous affiliations of Jerome Tamburini include Paris Descartes University & French Institute of Health and Medical Research.


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Journal ArticleDOI
Daniel J. Klionsky1, Kotb Abdelmohsen2, Akihisa Abe3, Joynal Abedin4  +2519 moreInstitutions (695)
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

5,187 citations

Journal ArticleDOI
Elizabeth C. Townsend1, Mark A. Murakami1, Alexandra N. Christodoulou1, Amanda L. Christie1, Johannes Köster1, Tiffany DeSouza1, Elizabeth A. Morgan2, Scott P. Kallgren1, Huiyun Liu1, Shuo-Chieh Wu1, Olivia Plana1, Joan Montero1, Kristen E. Stevenson1, Prakash Rao1, Raga Vadhi1, Michael Andreeff3, Philippe Armand1, Karen K. Ballen1, Patrizia Barzaghi-Rinaudo4, Sarah Cahill1, Rachael A. Clark2, Vesselina G. Cooke4, Matthew S. Davids1, Daniel J. DeAngelo1, David M. Dorfman2, Hilary Eaton1, Benjamin L. Ebert2, Julia Etchin1, Brant Firestone4, David C. Fisher1, Arnold S. Freedman1, Ilene Galinsky1, Hui Gao4, Jacqueline S. Garcia1, Francine Garnache-Ottou5, Timothy A. Graubert1, Alejandro Gutierrez6, Alejandro Gutierrez1, Ensar Halilovic4, Marian H. Harris6, Zachary T. Herbert1, Steven M. Horwitz7, Giorgio Inghirami8, Andrew M. Intlekofer7, Moriko Ito4, Shai Izraeli9, Eric D. Jacobsen1, Caron A. Jacobson1, Sébastien Jeay4, Irmela Jeremias10, Michelle A. Kelliher11, Raphael Koch1, Marina Konopleva3, Nadja Kopp1, Steven M. Kornblau3, Andrew L. Kung12, Thomas S. Kupper2, Nicole R. LeBoeuf2, Ann S. LaCasce1, Emma Lees4, Loretta S. Li1, A. Thomas Look1, Masato Murakami4, Markus Müschen13, Donna Neuberg1, Samuel Y. Ng1, Oreofe O. Odejide1, Stuart H. Orkin1, Rachel R. Paquette1, Andrew E. Place1, Justine E. Roderick11, Jeremy Ryan1, Stephen E. Sallan1, Brent Shoji2, Lewis B. Silverman1, Robert J. Soiffer1, David P. Steensma1, Kimberly Stegmaier1, Richard Stone1, Jerome Tamburini14, Aaron R. Thorner1, Paul Van Hummelen1, Martha Wadleigh1, Marion Wiesmann4, Andrew P. Weng, Jens Wuerthner4, David A. Williams12, Bruce M. Wollison1, Andrew A. Lane1, Anthony Letai1, Monica M. Bertagnolli13, Jerome Ritz1, Myles Brown1, Henry W. Long1, Jon C. Aster2, Margaret A. Shipp1, James D. Griffin1, David M. Weinstock1, David M. Weinstock15 
TL;DR: It is demonstrated that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.

261 citations

Journal ArticleDOI
TL;DR: The results open the way for the design of direct inhibitors of protein synthesis as novel acute myeloid leukemia therapies and also for the development of second generation mTOR inhibitors (the TORKinhibs).
Abstract: The PI3K/AKT and mTOR signaling pathways are activated in acute myeloid leukemia, including in the more immature leukemic populations. Constitutive PI3K activation is detectable in 50% of acute myeloid leukemia samples whereas mTORC1 is activated in all cases of this disease. In leukemic cells, the PI3K activity relates to the expression of the p110δ isoform of class IA PI3K. Constitutive PI3K activation is the result of autocrine IGF-1/IGF-1R signaling in 70% of acute myeloid leukemia samples but specific inhibition of this pathway does not induce apoptosis. Specific inhibition of PI3K/AKT or mTORC1 alone in vitro has anti-leukemic effects which are essentially exerted via the suppression of proliferation. However, as mTORC1 activation is independent of PI3K/AKT in acute myeloid leukemia, dual PI3K and mTOR inhibitors may induce apoptosis in blast cells. Moreover, mTORC1 inhibition using sirolimus overactivates PI3K/AKT via the upregulation of IRS2 expression and by favoring IGF-1/IGF-1R autocrine signaling. Recent data also indicate that mTORC1 does not control protein translation in acute myeloid leukemia. These results open the way for the design of direct inhibitors of protein synthesis as novel acute myeloid leukemia therapies and also for the development of second generation mTOR inhibitors (the TORKinhibs).

254 citations


Cited by
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Lorenzo Galluzzi1, Lorenzo Galluzzi2, Ilio Vitale3, Stuart A. Aaronson4  +183 moreInstitutions (111)
TL;DR: The Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives.
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

3,301 citations

Journal Article
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore PL02-05 All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

2,737 citations

Journal ArticleDOI
TL;DR: A functional classification of cell death subroutines is proposed that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic programmed cell death, regulated necrosis, autophagic cell death and mitotic catastrophe.
Abstract: In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

2,238 citations

Journal ArticleDOI
TL;DR: A way forward is suggested for the effective targeting of autophagy by understanding the context-dependent roles of autophile and by capitalizing on modern approaches to clinical trial design.
Abstract: Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

1,606 citations

Journal ArticleDOI
TL;DR: The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus, which will undoubtedly inform the rational design of novel therapies.
Abstract: Phosphatase and tensin homologue (PTEN) governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture Unravelling its enzymatic activities, its signalling partners, and the molecular mechanisms involved in the multiple levels of PTEN regulation will aid the design of novel PTEN-based therapeutic interventions in cancer The importance of the physiological function of phosphatase and tensin homologue (PTEN) is illustrated by its frequent disruption in cancer By suppressing the phosphoinositide 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity, PTEN governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture Consequently, mechanisms regulating PTEN expression and function, including transcriptional regulation, post-transcriptional regulation by non-coding RNAs, post-translational modifications and protein–protein interactions, are all altered in cancer The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus Our increasing knowledge of PTEN and pathologies in which its function is altered will undoubtedly inform the rational design of novel therapies

1,593 citations