15 research outputs found
Les mĂ©moires de maĂźtrise en service social Ă l'UniversitĂ© d'Ottawa et Ă lâUniversitĂ© Laurentienne
Bone marrow graft versus peripheral blood graft in haploidentical hematopoietic stem cells transplantation: a retrospective analysis in1344 patients of SFGM-TC registry.
peer reviewedThe use of peripheral blood (PB) or bone marrow (BM) stem cells graft in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis remains controversial. Moreover, the value of adding anti-thymoglobulin (ATG) to PTCy is unknown. A total of 1344 adult patients received an unmanipulated haploidentical transplant at 37 centers from 2012 to 2019 for hematologic malignancy. We compared the outcomes of patients according to the type of graft, using a propensity score analysis. In total population, grade II-IV and III-IV acute GVHD (aGVHD) were lower with BM than with PB. Grade III-IV aGVHD was lower with BM than with PBâ+âATG. All outcomes were similar in PB and PBâ+âATG groups. Then, in total population, adding ATG does not benefit the procedure. In acute leukemia, myelodysplastic syndrome and myeloproliferative syndrome (AL-MDS-MPS) subgroup receiving non-myeloablative conditioning, risk of relapse was twice greater with BM than with PB (51 vs. 22%, respectively). Conversely, risk of aGVHD was greater with PB (38% for aGVHD II-IV; 16% for aGVHD III-IV) than with BM (28% for aGVHD II-IV; 8% for aGVHD III-IV). In this subgroup with intensified conditioning regimen, risk of relapse became similar with PB and BM but risk of aGVHD III-IV remained higher with PB than with BM graft (HRâ=â2.0; range [1.17-3.43], pâ=â0.012)
Glutamine metabolism in acute myeloid leukemia
La survie des cellules cancĂ©reuses dĂ©pend dâune activitĂ© Ă©nergĂ©tique et biosynthĂ©tique accrue et la glutamine participe Ă de nombreux processus nĂ©cessaires Ă cette adaptation mĂ©tabolique. Dans les leucĂ©mies aiguĂ«s myĂ©loĂŻdes (LAM), la croissance et la prolifĂ©ration sont favorisĂ©es par lâactivation anormale de plusieurs voies de signalisation, et notamment par la voie mTORC1. Les acides aminĂ©s essentiels, et en particulier la leucine, sont indispensables Ă lâactivation de mTORC1. La glutamine est captĂ©e par la cellule via le transporteur SLC1A5 et permet ensuite lâentrĂ©e de la leucine via le transporteur bidirectionnel SLC7A5. La concentration en glutamine est donc une Ă©tape limitante dans lâactivation de mTORC1 par la leucine. Nous avons Ă©tudiĂ© les effets de la privation en glutamine dans les LAM Ă lâaide de diffĂ©rents outils (milieu sans glutamine, shARN inhibant lâexpression du transporteur de la glutamine SLC1A5 et la drogue L-asparaginase, qui a une activitĂ© de glutaminase extracellulaire), et observĂ© une inhibition de mTORC1 et de la synthĂšse protĂ©ique. Lâinhibition du transporteur SLC1A5 inhibe la pousse tumorale dans un modĂšle de xĂ©notransplantation. La L-asparaginase inhibe mTORC1 et induit une apoptose de façon proportionnelle Ă son activitĂ© glutaminase et complĂštement indĂ©pendante de la concentration en asparagine. La privation en glutamine induit lâexpression de la glutamine synthase et lâautophagie, et ces deux processus peuvent ĂȘtre des mĂ©canismes de rĂ©sistance intrinsĂšques ou acquis dans certaines lignĂ©es leucĂ©miques. Lâapoptose induite par la privation en glutamine nâest cependant pas liĂ©e Ă lâinhibition de mTORC1, puisquâelle nâest pas diminuĂ©e par lâutilisation dâun mutant de mTOR non inhibĂ© par la privation en glutamine. Nous nous sommes donc intĂ©ressĂ©s Ă une autre voie dĂ©pendante de la glutamine dans de nombreux cancers, la phosphorylation oxydative. LâĂ©tape initiale du catabolisme intracellulaire de la glutamine est la conversion de la glutamine en glutamate par des enzymes appelĂ©es glutaminases. DiffĂ©rentes isoformes des glutaminases existent qui sont codĂ©es chez lâhomme par les gĂšnes GLS1 et GLS2. Le glutamate est ensuite transformĂ© en α-cĂ©toglutarate, intermĂ©diaire du cycle TCA. Dans les lignĂ©es de LAM, la privation en glutamine inhibe la phosphorylation oxydative mitochondriale. Nous avons observĂ© que la protĂ©ine glutaminase C (GAC), une des isoformes de GLS1, est constamment exprimĂ©e dans les LAM mais aussi dans les progĂ©niteurs hĂ©matopoĂŻĂ©tiques CD34+ normaux. Lâinhibition dâexpression de la GLS1 par des shARN inductibles ou bien par le composĂ© CB-839 rĂ©duit la phosphorylation oxydative, conduisant Ă une inhibition de prolifĂ©ration et Ă une induction dâapoptose des cellules leucĂ©miques. Lâinvalidation gĂ©nĂ©tique de la GLS1 inhibe la formation de tumeur et amĂ©liore la survie des souris dans un modĂšle de xĂ©notransplantation. A lâinverse, le ciblage de la GLS1 nâa pas dâeffets cytotoxiques ni cytostatiques sur les progĂ©niteurs hĂ©matopoĂŻĂ©tiques normaux. Ces effets anti-leucĂ©miques sont inhibĂ©s par lâadjonction dâα-cĂ©toglutarate, et ceux induit par le CB-839 sont abrogĂ©s lorsquâest exprimĂ© de façon ectopique un mutant GACK320A hyperactif, attestant du rĂŽle essentiel du maintien dâun cycle TCA actif dans les cellules de LAM. Enfin, nous montrons que lâinhibition de la glutaminolyse active la voie dâapoptose mitochondriale intrinsĂšque et agit en synergie avec lâinhibition spĂ©cifique de BCL-2 par lâABT-199. Ces rĂ©sultats dĂ©montrent que le ciblage spĂ©cifique de la glutaminolyse est une autre façon dâexploiter lâaddiction Ă la glutamine des cellules leucĂ©miques de LAM et que le maintien dâun cycle TCA actif est essentiel Ă la survie de ces cellules.Cancer cells survival is dependent on high energetic and biosynthetic activity, and glutamine is involved in many metabolic processes necessary for this adaptation. In acute myeloid leukemia (AML), growth and proliferation are promoted by activation of several signaling pathways, including mTORC1. Essential amino acids, in particular leucine, are required for mTORC1 activation. Glutamine enters into the cell via the SLC1A5 transporter and then allows the input of leucine via the bidirectional SLC7A5 transporter. Therefore, the intracellular glutamine concentration is a limiting step in the activation of mTORC1 by leucine. We studied the effects of glutamine deprivation in AML using different tools (medium without glutamine, shRNA against the SLC1A5 glutamine transporter and the drug L-asparaginase, which has an extracellular glutaminase activity) and observed mTORC1 and protein synthesis inhibition. SLC1A5 transporter knockdown inhibits tumor growth in a xenotransplantation model. L-asparaginase inhibits mTORC1 and induces apoptosis in proportion to its glutaminase activity and independently of asparagine concentration. Glutamine privation induces the expression of glutamine synthase and autophagy, and these two processes are involved in the resistance to glutamine privation in some leukemic cell lines. However, apoptosis induced by glutamine privation is not related to the inhibition of mTORC1, since it is not modified in the presence of a constitutively active mutant of mTOR. We next focused on the oxidative phosphorylation, another glutamine dependent pathway in many cancers. The initial step of the intracellular catabolism of glutamine is the conversion of glutamine to glutamate by enzymes called glutaminases. Different glutaminases isoforms exist that are encoded by the GLS1 and GLS2 genes. Glutamate is then converted to α-ketoglutarate, an essential TCA cycle intermediate. In AML cell lines, we observed that glutamine privation inhibits mitochondrial oxidative phosphorylation. The protein glutaminase C (GAC), an isoform of GLS1, is constantly expressed in AML but also in normal CD34 + hematopoietic progenitors. The knockdown of GLS1 by inducible shRNA or by the CB-839 compound reduced oxidative phosphorylation, leading to proliferation inhibition and apoptosis induction in leukemia cells. Genetic invalidation of GLS1 inhibits tumor formation and improves survival of mice in a xenograft model. Conversely, the targeting of GLS1 has no cytotoxic or cytostatic effects on normal hematopoietic progenitors. These anti-leukemic effects are inhibited by the addition of α-ketoglutarate, and those induced by the CB-839 are suppressed in the presence of an ectopically expressed GACK320A hyperactive mutant, confirming the essential role of maintaining an active TCA cycle in AML cells. Finally, we showed that glutaminolysis inhibition induces the intrinsic mitochondrial pathway of apoptosis and acts synergistically with the specific inhibition of BCL-2 by ABT-199. These results demonstrate that specific targeting of glutaminolysis is another way to exploit glutamine addiction in AML and that an active TCA cycle in essential for AML cell survival
Ătude du mĂ©tabolisme de la glutamine dans les leucĂ©mies aiguĂ«s myĂ©loĂŻdes
Cancer cells survival is dependent on high energetic and biosynthetic activity, and glutamine is involved in many metabolic processes necessary for this adaptation. In acute myeloid leukemia (AML), growth and proliferation are promoted by activation of several signaling pathways, including mTORC1. Essential amino acids, in particular leucine, are required for mTORC1 activation. Glutamine enters into the cell via the SLC1A5 transporter and then allows the input of leucine via the bidirectional SLC7A5 transporter. Therefore, the intracellular glutamine concentration is a limiting step in the activation of mTORC1 by leucine. We studied the effects of glutamine deprivation in AML using different tools (medium without glutamine, shRNA against the SLC1A5 glutamine transporter and the drug L-asparaginase, which has an extracellular glutaminase activity) and observed mTORC1 and protein synthesis inhibition. SLC1A5 transporter knockdown inhibits tumor growth in a xenotransplantation model. L-asparaginase inhibits mTORC1 and induces apoptosis in proportion to its glutaminase activity and independently of asparagine concentration. Glutamine privation induces the expression of glutamine synthase and autophagy, and these two processes are involved in the resistance to glutamine privation in some leukemic cell lines. However, apoptosis induced by glutamine privation is not related to the inhibition of mTORC1, since it is not modified in the presence of a constitutively active mutant of mTOR. We next focused on the oxidative phosphorylation, another glutamine dependent pathway in many cancers. The initial step of the intracellular catabolism of glutamine is the conversion of glutamine to glutamate by enzymes called glutaminases. Different glutaminases isoforms exist that are encoded by the GLS1 and GLS2 genes. Glutamate is then converted to α-ketoglutarate, an essential TCA cycle intermediate. In AML cell lines, we observed that glutamine privation inhibits mitochondrial oxidative phosphorylation. The protein glutaminase C (GAC), an isoform of GLS1, is constantly expressed in AML but also in normal CD34 + hematopoietic progenitors. The knockdown of GLS1 by inducible shRNA or by the CB-839 compound reduced oxidative phosphorylation, leading to proliferation inhibition and apoptosis induction in leukemia cells. Genetic invalidation of GLS1 inhibits tumor formation and improves survival of mice in a xenograft model. Conversely, the targeting of GLS1 has no cytotoxic or cytostatic effects on normal hematopoietic progenitors. These anti-leukemic effects are inhibited by the addition of α-ketoglutarate, and those induced by the CB-839 are suppressed in the presence of an ectopically expressed GACK320A hyperactive mutant, confirming the essential role of maintaining an active TCA cycle in AML cells. Finally, we showed that glutaminolysis inhibition induces the intrinsic mitochondrial pathway of apoptosis and acts synergistically with the specific inhibition of BCL-2 by ABT-199. These results demonstrate that specific targeting of glutaminolysis is another way to exploit glutamine addiction in AML and that an active TCA cycle in essential for AML cell survival.La survie des cellules cancĂ©reuses dĂ©pend dâune activitĂ© Ă©nergĂ©tique et biosynthĂ©tique accrue et la glutamine participe Ă de nombreux processus nĂ©cessaires Ă cette adaptation mĂ©tabolique. Dans les leucĂ©mies aiguĂ«s myĂ©loĂŻdes (LAM), la croissance et la prolifĂ©ration sont favorisĂ©es par lâactivation anormale de plusieurs voies de signalisation, et notamment par la voie mTORC1. Les acides aminĂ©s essentiels, et en particulier la leucine, sont indispensables Ă lâactivation de mTORC1. La glutamine est captĂ©e par la cellule via le transporteur SLC1A5 et permet ensuite lâentrĂ©e de la leucine via le transporteur bidirectionnel SLC7A5. La concentration en glutamine est donc une Ă©tape limitante dans lâactivation de mTORC1 par la leucine. Nous avons Ă©tudiĂ© les effets de la privation en glutamine dans les LAM Ă lâaide de diffĂ©rents outils (milieu sans glutamine, shARN inhibant lâexpression du transporteur de la glutamine SLC1A5 et la drogue L-asparaginase, qui a une activitĂ© de glutaminase extracellulaire), et observĂ© une inhibition de mTORC1 et de la synthĂšse protĂ©ique. Lâinhibition du transporteur SLC1A5 inhibe la pousse tumorale dans un modĂšle de xĂ©notransplantation. La L-asparaginase inhibe mTORC1 et induit une apoptose de façon proportionnelle Ă son activitĂ© glutaminase et complĂštement indĂ©pendante de la concentration en asparagine. La privation en glutamine induit lâexpression de la glutamine synthase et lâautophagie, et ces deux processus peuvent ĂȘtre des mĂ©canismes de rĂ©sistance intrinsĂšques ou acquis dans certaines lignĂ©es leucĂ©miques. Lâapoptose induite par la privation en glutamine nâest cependant pas liĂ©e Ă lâinhibition de mTORC1, puisquâelle nâest pas diminuĂ©e par lâutilisation dâun mutant de mTOR non inhibĂ© par la privation en glutamine. Nous nous sommes donc intĂ©ressĂ©s Ă une autre voie dĂ©pendante de la glutamine dans de nombreux cancers, la phosphorylation oxydative. LâĂ©tape initiale du catabolisme intracellulaire de la glutamine est la conversion de la glutamine en glutamate par des enzymes appelĂ©es glutaminases. DiffĂ©rentes isoformes des glutaminases existent qui sont codĂ©es chez lâhomme par les gĂšnes GLS1 et GLS2. Le glutamate est ensuite transformĂ© en α-cĂ©toglutarate, intermĂ©diaire du cycle TCA. Dans les lignĂ©es de LAM, la privation en glutamine inhibe la phosphorylation oxydative mitochondriale. Nous avons observĂ© que la protĂ©ine glutaminase C (GAC), une des isoformes de GLS1, est constamment exprimĂ©e dans les LAM mais aussi dans les progĂ©niteurs hĂ©matopoĂŻĂ©tiques CD34+ normaux. Lâinhibition dâexpression de la GLS1 par des shARN inductibles ou bien par le composĂ© CB-839 rĂ©duit la phosphorylation oxydative, conduisant Ă une inhibition de prolifĂ©ration et Ă une induction dâapoptose des cellules leucĂ©miques. Lâinvalidation gĂ©nĂ©tique de la GLS1 inhibe la formation de tumeur et amĂ©liore la survie des souris dans un modĂšle de xĂ©notransplantation. A lâinverse, le ciblage de la GLS1 nâa pas dâeffets cytotoxiques ni cytostatiques sur les progĂ©niteurs hĂ©matopoĂŻĂ©tiques normaux. Ces effets anti-leucĂ©miques sont inhibĂ©s par lâadjonction dâα-cĂ©toglutarate, et ceux induit par le CB-839 sont abrogĂ©s lorsquâest exprimĂ© de façon ectopique un mutant GACK320A hyperactif, attestant du rĂŽle essentiel du maintien dâun cycle TCA actif dans les cellules de LAM. Enfin, nous montrons que lâinhibition de la glutaminolyse active la voie dâapoptose mitochondriale intrinsĂšque et agit en synergie avec lâinhibition spĂ©cifique de BCL-2 par lâABT-199. Ces rĂ©sultats dĂ©montrent que le ciblage spĂ©cifique de la glutaminolyse est une autre façon dâexploiter lâaddiction Ă la glutamine des cellules leucĂ©miques de LAM et que le maintien dâun cycle TCA actif est essentiel Ă la survie de ces cellules
Ătude du mĂ©tabolisme de la glutamine dans les leucĂ©mies aiguĂ«s myĂ©loĂŻdes
Cancer cells survival is dependent on high energetic and biosynthetic activity, and glutamine is involved in many metabolic processes necessary for this adaptation. In acute myeloid leukemia (AML), growth and proliferation are promoted by activation of several signaling pathways, including mTORC1. Essential amino acids, in particular leucine, are required for mTORC1 activation. Glutamine enters into the cell via the SLC1A5 transporter and then allows the input of leucine via the bidirectional SLC7A5 transporter. Therefore, the intracellular glutamine concentration is a limiting step in the activation of mTORC1 by leucine. We studied the effects of glutamine deprivation in AML using different tools (medium without glutamine, shRNA against the SLC1A5 glutamine transporter and the drug L-asparaginase, which has an extracellular glutaminase activity) and observed mTORC1 and protein synthesis inhibition. SLC1A5 transporter knockdown inhibits tumor growth in a xenotransplantation model. L-asparaginase inhibits mTORC1 and induces apoptosis in proportion to its glutaminase activity and independently of asparagine concentration. Glutamine privation induces the expression of glutamine synthase and autophagy, and these two processes are involved in the resistance to glutamine privation in some leukemic cell lines. However, apoptosis induced by glutamine privation is not related to the inhibition of mTORC1, since it is not modified in the presence of a constitutively active mutant of mTOR. We next focused on the oxidative phosphorylation, another glutamine dependent pathway in many cancers. The initial step of the intracellular catabolism of glutamine is the conversion of glutamine to glutamate by enzymes called glutaminases. Different glutaminases isoforms exist that are encoded by the GLS1 and GLS2 genes. Glutamate is then converted to α-ketoglutarate, an essential TCA cycle intermediate. In AML cell lines, we observed that glutamine privation inhibits mitochondrial oxidative phosphorylation. The protein glutaminase C (GAC), an isoform of GLS1, is constantly expressed in AML but also in normal CD34 + hematopoietic progenitors. The knockdown of GLS1 by inducible shRNA or by the CB-839 compound reduced oxidative phosphorylation, leading to proliferation inhibition and apoptosis induction in leukemia cells. Genetic invalidation of GLS1 inhibits tumor formation and improves survival of mice in a xenograft model. Conversely, the targeting of GLS1 has no cytotoxic or cytostatic effects on normal hematopoietic progenitors. These anti-leukemic effects are inhibited by the addition of α-ketoglutarate, and those induced by the CB-839 are suppressed in the presence of an ectopically expressed GACK320A hyperactive mutant, confirming the essential role of maintaining an active TCA cycle in AML cells. Finally, we showed that glutaminolysis inhibition induces the intrinsic mitochondrial pathway of apoptosis and acts synergistically with the specific inhibition of BCL-2 by ABT-199. These results demonstrate that specific targeting of glutaminolysis is another way to exploit glutamine addiction in AML and that an active TCA cycle in essential for AML cell survival.La survie des cellules cancĂ©reuses dĂ©pend dâune activitĂ© Ă©nergĂ©tique et biosynthĂ©tique accrue et la glutamine participe Ă de nombreux processus nĂ©cessaires Ă cette adaptation mĂ©tabolique. Dans les leucĂ©mies aiguĂ«s myĂ©loĂŻdes (LAM), la croissance et la prolifĂ©ration sont favorisĂ©es par lâactivation anormale de plusieurs voies de signalisation, et notamment par la voie mTORC1. Les acides aminĂ©s essentiels, et en particulier la leucine, sont indispensables Ă lâactivation de mTORC1. La glutamine est captĂ©e par la cellule via le transporteur SLC1A5 et permet ensuite lâentrĂ©e de la leucine via le transporteur bidirectionnel SLC7A5. La concentration en glutamine est donc une Ă©tape limitante dans lâactivation de mTORC1 par la leucine. Nous avons Ă©tudiĂ© les effets de la privation en glutamine dans les LAM Ă lâaide de diffĂ©rents outils (milieu sans glutamine, shARN inhibant lâexpression du transporteur de la glutamine SLC1A5 et la drogue L-asparaginase, qui a une activitĂ© de glutaminase extracellulaire), et observĂ© une inhibition de mTORC1 et de la synthĂšse protĂ©ique. Lâinhibition du transporteur SLC1A5 inhibe la pousse tumorale dans un modĂšle de xĂ©notransplantation. La L-asparaginase inhibe mTORC1 et induit une apoptose de façon proportionnelle Ă son activitĂ© glutaminase et complĂštement indĂ©pendante de la concentration en asparagine. La privation en glutamine induit lâexpression de la glutamine synthase et lâautophagie, et ces deux processus peuvent ĂȘtre des mĂ©canismes de rĂ©sistance intrinsĂšques ou acquis dans certaines lignĂ©es leucĂ©miques. Lâapoptose induite par la privation en glutamine nâest cependant pas liĂ©e Ă lâinhibition de mTORC1, puisquâelle nâest pas diminuĂ©e par lâutilisation dâun mutant de mTOR non inhibĂ© par la privation en glutamine. Nous nous sommes donc intĂ©ressĂ©s Ă une autre voie dĂ©pendante de la glutamine dans de nombreux cancers, la phosphorylation oxydative. LâĂ©tape initiale du catabolisme intracellulaire de la glutamine est la conversion de la glutamine en glutamate par des enzymes appelĂ©es glutaminases. DiffĂ©rentes isoformes des glutaminases existent qui sont codĂ©es chez lâhomme par les gĂšnes GLS1 et GLS2. Le glutamate est ensuite transformĂ© en α-cĂ©toglutarate, intermĂ©diaire du cycle TCA. Dans les lignĂ©es de LAM, la privation en glutamine inhibe la phosphorylation oxydative mitochondriale. Nous avons observĂ© que la protĂ©ine glutaminase C (GAC), une des isoformes de GLS1, est constamment exprimĂ©e dans les LAM mais aussi dans les progĂ©niteurs hĂ©matopoĂŻĂ©tiques CD34+ normaux. Lâinhibition dâexpression de la GLS1 par des shARN inductibles ou bien par le composĂ© CB-839 rĂ©duit la phosphorylation oxydative, conduisant Ă une inhibition de prolifĂ©ration et Ă une induction dâapoptose des cellules leucĂ©miques. Lâinvalidation gĂ©nĂ©tique de la GLS1 inhibe la formation de tumeur et amĂ©liore la survie des souris dans un modĂšle de xĂ©notransplantation. A lâinverse, le ciblage de la GLS1 nâa pas dâeffets cytotoxiques ni cytostatiques sur les progĂ©niteurs hĂ©matopoĂŻĂ©tiques normaux. Ces effets anti-leucĂ©miques sont inhibĂ©s par lâadjonction dâα-cĂ©toglutarate, et ceux induit par le CB-839 sont abrogĂ©s lorsquâest exprimĂ© de façon ectopique un mutant GACK320A hyperactif, attestant du rĂŽle essentiel du maintien dâun cycle TCA actif dans les cellules de LAM. Enfin, nous montrons que lâinhibition de la glutaminolyse active la voie dâapoptose mitochondriale intrinsĂšque et agit en synergie avec lâinhibition spĂ©cifique de BCL-2 par lâABT-199. Ces rĂ©sultats dĂ©montrent que le ciblage spĂ©cifique de la glutaminolyse est une autre façon dâexploiter lâaddiction Ă la glutamine des cellules leucĂ©miques de LAM et que le maintien dâun cycle TCA actif est essentiel Ă la survie de ces cellules
Targeting glutamine uptake in AML.
International audienceCancer cells require nutrients and energy to adapt to increased biosynthetic activity and depend on mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis. Whereas they exhibit a pronounced Warburg effect, their TCA cycle remains intact and becomes more dependent on glutamine metabolism through glutaminolysis[1]. Besides this role, intracellular glutamine is also essential for mTORC1 activation by leucine[2]. Many upstream signals regulate mTORC1 activation. Among them, a major process is the availability of leucine, which is required to activate the Rag (for Ras-related GTPases) proteins that enable the proper localization of mTORC1 at the lysosome surface close to its activator Rheb[3]. Leucine uptake into the cells is regulated by the bidirectional transporter SLC7A5/3A2, in exchange for glutamine. The level of leucine thereby depends on the intracellular glutamine concentrations, which is mainly mediated by the high affinity transporter SLC1A5. Thus, the cellular uptake and subsequent rapid efflux of glutamine in the presence of leucine make glutamine availability a limiting step for the activation of mTORC1. MTORC1 positively regulates protein translation through phosphorylation of protein S6 Kinase (P70S6K) and eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). Protein synthesis is controlled by the translational repressor 4E-BP1 whose phosphorylation at serine 65 is required to initiate the formation of the translation initiation complex. The dependence of acute myeloid leukemia (AML) cells to glutamine is little studied. In a recent work, we have tested the effects of glutamine depletion in AML cells[4]: leukemic cells are sensitive to glutamine removal leading to mTORC1 inhibition and apoptosis. The drug L-asparaginase (L-ase) also inhibits mTORC1 activity in AML cells, suppresses protein synthesis and induces apoptosis. The anti-leukemic effects of the two clinically available forms of L-ase, E Coli L-ase (KidrolaseÂź) and E. Chrysanthemi L-ase (ErwiniaseÂź) are not mediated by the asparaginase activity of the enzyme. L-ases have also a glutaminase activity and transform extracellular glutamine into glutamate. Both L-ases induce dose and time-dependent mTORC1-inhibition which correlates with extra-cellular glutamine depletion[4]. Downstream of mTORC1, L-ase suppresses 4E-BP1 phosphorylation and inhibits [S 3
Plasmacytoid dendritic cells respond to Epstein-Barr virus infection with a distinct type I interferon subtype profile
Infectious mononucleosis, caused by infection with the human gamma-herpesvirus Epstein-Barr virus (EBV), manifests with one of the strongest CD8 T-cell responses described in humans. The resulting T-cell memory response controls EBV infection asymptomatically in the vast majority of persistently infected individuals. Whether and how dendritic cells (DCs) contribute to the priming of this near-perfect immune control remains unclear. Here we show that of all the human DC subsets, plasmacytoid DCs (pDCs) play a central role in the detection of EBV infection in vitro and in mice with reconstituted human immune system components. pDCs respond to EBV by producing the interferon (IFN) subtypes α1, α2, α5, α7, α14, and α17. However, the virus curtails this type I IFN production with its latent EBV gene products EBNA3A and EBNA3C. The induced type I IFNs inhibit EBV entry and the proliferation of latently EBV-transformed B cells but do not influence lytic reactivation of the virus in vitro. In vivo, exogenous IFN-α14 and IFN-α17, as well as pDC expansion, delay EBV infection and the resulting CD8 T-cell expansion, but pDC depletion does not significantly influence EBV infection. Thus, consistent with the observation that primary immunodeficiencies compromising type I IFN responses affect only alpha- and beta-herpesvirus infections, we found that EBV elicits pDC responses that transiently suppress viral replication and attenuate CD8 T-cell expansion but are not required to control primary infection
Inflammation in Waldenström macroglobulinemia is associated with 6q deletion and need for treatment initiation
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Comparative Natural History of Visual Function From Patients With Biallelic Variants in BBS1 and BBS10.
Purpose: The purpose of this study was to compare the natural history of visual function change in cohorts of patients affected with retinal degeneration due to biallelic variants in Bardet-Biedl syndrome genes: BBS1 and BBS10. Methods: Patients were recruited from nine academic centers from six countries (Belgium, Canada, France, New Zealand, Switzerland, and the United States). Inclusion criteria were: (1) female or male patients with a clinical diagnosis of retinal dystrophy, (2) biallelic disease-causing variants in BBS1 or BBS10, and (3) measures of visual function for at least one visit. Retrospective data collected included genotypes, age, onset of symptoms, and best corrected visual acuity (VA). When possible, data on refractive error, fundus images and autofluorescence (FAF), optical coherence tomography (OCT), Goldmann kinetic perimetry (VF), electroretinography (ERG), and the systemic phenotype were collected. Results: Sixty-seven individuals had variants in BBS1 (n = 38; 20 female patients and 18 male patients); or BBS10 (n = 29; 14 female patients and 15 male patients). Missense variants were the most common type of variants for patients with BBS1, whereas frameshift variants were most common for BBS10. When ERGs were recordable, rod-cone dystrophy (RCD) was observed in 82% (23/28) of patients with BBS1 and 73% (8/11) of patients with BBS10; cone-rod dystrophy (CORD) was seen in 18% of patients with BBS1 only, and cone dystrophy (COD) was only seen in 3 patients with BBS10 (27%). ERGs were nondetectable earlier in patients with BBS10 than in patients with BBS1. Similarly, VA and VF declined more rapidly in patients with BBS10 compared to patients with BBS1. Conclusions: Retinal degeneration appears earlier and is more severe in BBS10 cases as compared to those with BBS1 variants. The course of change of visual function appears to relate to genetic subtypes of BBS