GAPDH Expression Predicts the Response to R-CHOP, the Tumor Metabolic Status, and the Response of DLBCL Patients to Metabolic Inhibitors

被引：55

作者：

Chiche, Johanna ^{[1
]}

Reverso-Meinietti, Julie ^{[1
,2
]}

Mouchotte, Annabelle ^{[1
]}

Rubio-Patino, Camila ^{[1
]}

Mhaidly, Rana ^{[1
]}

Villa, Elodie ^{[1
]}

Bossowski, Jozef P. ^{[1
]}

Proics, Emma ^{[1
]}

Grima-Reyes, Manuel ^{[1
]}

Paquet, Agnes ^{[3
]}

Fragaki, Konstantina ^{[4
,5
,6
]}

Marchetti, Sandrine ^{[1
]}

Briere, Josette ^{[7
]}

Ambrosetti, Damien ^{[2
,5
]}

Michiels, Jean-Francois ^{[2
,4
]}

Molina, Thierry Jo ^{[8
]}

Copie-Bergman, Christiane ^{[9
]}

Lehmann-Che, Jacqueline ^{[10
]}

Peyrottes, Isabelle ^{[11
]}

Peyrade, Frederic ^{[11
]}

de Kerviler, Eric ^{[12
]}

Taillan, Bruno ^{[13
]}

Garnier, Georges ^{[13
]}

Verhoeyen, Els ^{[1
]}

Paquis-Flucklinger, Veronique ^{[4
,5
,6
]}

Shintu, Laetitia ^{[14
]}

Delwail, Vincent ^{[15
]}

Delpech-Debiais, Celine ^{[16
]}

Delarue, Richard ^{[17
]}

Bosly, Andre ^{[18
]}

Petrella, Tony ^{[19
]}

Brisou, Gabriel ^{[20
]}

Nadel, Bertrand ^{[20
]}

Barbry, Pascal ^{[3
]}

Mounier, Nicolas ^{[21
]}

Thieblemont, Catherine ^{[7
,22
]}

Ricci, Jean-Ehrland ^{[1
]}

机构：

[1] Univ Cote dAzur, C3M, INSERM, Nice, France

[2] CHU Nice, Lab Cent AnatomocytoPathol LCAP, Nice, France

[3] Univ Cote dAzur, Inst Pharmacol Mol & Cellulaire, CNRS, F-06560 Sophia Antipolis, France

[4] Univ Cote dAzur, Nice, France

[5] Nice Sophia Antipolis Univ, Sch Med, IRCAN, UMR CNRS 7284,INSERM U1081,UNS, Nice, France

[6] Nice Teaching Hosp, Natl Ctr Mitochondria Dis, Dept Med Genet, Nice, France

[7] Univ Paris Diderot, Sorbonne Paris Cite, Hop St Louis, AP HP,Hematooncol, Paris, France

[8] Univ Paris 05, Dept Pathol, Sorbonne Paris Cite, Hop Necker,AP HP,EA 7324, Paris, France

[9] Paris Est Creteil Univ, Henri Mondor Hosp, AP HP, INSERM U955,Dept Pathol, Creteil, France

[10] Univ Paris Diderot, Unite Oncol Mol, Sorbonne Paris Cite, Hop St Louis,AP HP, F-75010 Paris, France

[11] Ctr Antoine Lacassagne, Nice, France

[12] Univ Paris Diderot, Serv Radiol, Sorbonne Paris Cite, Hop St Louis,AP HP, F-75010 Paris, France

[13] Ctr Hosp Princesse Grace Monaco, Monaco, Monaco

[14] Aix Marseille Univ, ISM2, Cent Marseille, CNRS, Marseille, France

[15] Univ Poitiers, Ctr Invest Clin, Serv Oncol Hematol & Therapie Cellulaire, CHU Poitiers,INSERM,CIC 1402, Poitiers, France

[16] CHU Univ Poitiers, Dept Pathol, Poitiers, France

[17] Hop Necker Enfants Malad, AP HP, Dept Hematol, Paris, France

[18] UcL Namur, CHU Dinant Godinne, Yvoir, Belgium

[19] Hop Maison Neuve Rosemont, Dept Pathol, Montreal, PQ, Canada

[20] Aix Marseille Univ, INSERM, CIML, CNRS, Marseille, France

[21] CHU Nice, Dept Oncohematol, Nice, France

[22] Univ Paris 05, Paris EA7324, Differenciat & Canc, NF KappaB, Paris, France

来源：

CELL METABOLISM | 2019年 / 29卷 / 06期

基金：

欧盟地平线“2020”;

关键词：

B-CELL LYMPHOMA; RITUXIMAB PLUS CYCLOPHOSPHAMIDE; IN-SITU HYBRIDIZATION; ELDERLY-PATIENTS; C-MYC; CANCER; CHEMOTHERAPY; BCL2; MTOR; CLASSIFICATION;

D O I：

10.1016/j.cmet.2019.02.002

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDH(low) lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism(phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDH(low) B cells and improve GAPDH(low) B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDH(high) B cell lymphomas. Ultimately, we selected four GAPDH(low) DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism-using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors.

引用

页码：1243 / +

页数：25

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