team 3.3 Isocitrate dehydrogenase and Metabolism in Acute Myeloid Leukemia Jean - Emmanuel Sarry Team RESIST@ML – Drug Resistance & Oncometabolism in Acute Myeloid Leukemia Cancer Research Center of Toulouse UMR1037 INSERM – Université Toulouse 3 Oncopole de Toulouse Talk KIDF– 14 Janvier 2016 – Paris
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team 3.3
Isocitrate dehydrogenase and Metabolism
in Acute Myeloid Leukemia
Jean-Emmanuel Sarry
Team RESIST@ML – Drug Resistance & Oncometabolism in Acute Myeloid Leukemia
Cancer Research Center of ToulouseUMR1037 INSERM – Université Toulouse 3
Oncopole de Toulouse
Talk KIDF– 14 Janvier 2016 – Paris
Vanden Heiden et al. Science. 2009.
Beyond Warburg: Metabolism is a new Hallmark of AML?
"Warburg effect”
Présentateur
Commentaires de présentation
Comme vous le savez tous, la reprogrammation du métabolisme est l'une des caractéristiques majeures des cellules cancéreuses; les cellules LAM ne dérogent pas à la règle. Bien au delà de l'effet Warburg, les cellules cancéreuses arborent des caractéristiques et dépendances métaboliques spécifiques, ce qui représente des enjeux thérapeutiques particulièrement intéressants
-Etomoxir, avocatin B, CPT1i, CT2 inhibitors: anti-AML activity or increase theapoptotic efficacy of agent arsenic trioxide.Samudio et al. 2010. Estan et al. 2014. Lee et al 2015. Riccardi et al. 2015. Wu et al. 2015. Sriskanthadevan et al 2015.
-Glutamine removal, SLC1A5 transporter knockdown or L-asparaginase:antileukemic activity in AML by altering GSH, inhibiting mTORC1, triggering astrong autophagic response and inducing apoptosis.
Willems et al. 2013; Goto et al. 2014; Jacque et al. 2015.
-2-Deoxy-Glucose: anti-AML activity through the inhibition of both glycolysis and N-linked glycosylation in AML with FLT3-ITD or KIT mutations.
Larrue et al. Mol. Cancer Thr. 2015.
-Dendrogenin A: anti-AML activity through the LXR-dependent modulation of the sterol metabolism.
Segala et al. Submitted. In collaboration with Team 12 (Poirot, INSERM, CRCT).
-Metformin: anti-AML activity through the induction of the Pasteur effect.Scotland et al. Leukemia. 2013.
Metabolism of Acute Myeloid Leukemia cells: new targets?
Présentateur
Commentaires de présentation
Ainsi, ces dernières années, différentes équipes, dont la nôtre, ont montré l'intérêt de cibler le métabolisme, que ce soit en inhibant la mitochondrie avec la metformin, en bloquant la glutaminolyse ou encore en ciblant la glycolyse..
Effect of Metformin (anti-diabetic drug) on AML cell metabolism
Quantitative metabolomics by LC-MS/MS:getting absolute concentrations
Metformin induces a metabolic reprogramming that leads to Pasteur effect
Acetyl-CoA
Isocit
Succinyl-CoASuccinate
Fumarate
Mal
Pyruvate
CitrateOAA
Glucose Consumption
Glutamate
GlutamineConsumption
Isocit
Citrate
a-KG
Acetyl-CoA
Malonyl-CoA
Fatty Acids
Glutamate
Acyl-CoA
Sterols
Lactate
a-KG
ACC
Acyl-CoAAcyl-Carnitines
CarnitineCPT1
PDH
SphingolipidsPhospholipids
2H2O ATPO2
VIII
IIIIV
Scotland et al. Leukemia. 2013.
METFORMIN
ATP TriglyceridesCholesterol
esters
Lipid Droplet
Proliferation arrestApoptosis
Présentateur
Commentaires de présentation
Figure 8A
Vanden Heiden et al. Science. 2009.
Beyond Warburg: Metabolism is a new Hallmark of AML?
Mardis et al. NEJM. 2009.
"Warburg effect”
Van Heiden et al. Science. 2009.
-IDH1/2 interconvert isocitrate and α−KG;
-One of the four NADPH producing enzymes (G6PDH, 6PGDH, ME).
-Generation of the NADPH required to sustain many anabolic pathways (fatty acid elongation, lipid synthesis and cholesterol synthesis) and for the regeneration of reduced glutathione and thioredoxin as cellular defense against oxidative damage.
Citrate
Isocitrate
Glutamine
α-KG
IDH-WT Cells
Succinate
Idh1/2NADPH
NADP+
Key functions of IDH-WT for anabolic metabolism & redox homeostasis
Pyruvate Acetyl-CoA
Isocit
Idh2 Idh1
Succinyl-CoASuccinate
Fumarate
Mal
1,3-DiPG
Pyruvate
GA3P
F6P
G6P
Ribu5P
6-PGG6pd
6-PGL
CitrateOAA
Glucose
Glutamate
Glutamine
Isocit
Citrate
α-KG
Acetyl-CoA
Malonyl-CoA
Fatty Acids
Glutamate
Mal
HMG-CoA SterolsIsoprenes
Lactate
OAA
α-KG
PEP
Idh1IDH2G6pdh6PgdhMe1
NADPHNADP
GSHGSSGGsr
Gpx1H2OH2O2
Me1
Pgd
Fh
Sdh
NADPH-producing enzymes
SphingoLipids
PhosphoLipidsGly-3PDHAP
3-PG Serine
Nucleotides
IDH1 is a crucial enzyme for NADPH production, glutathione regeneration and lipid/sterols synthesis while mitochondria altered
2H2O ATPO2
VIII
IIIIV
HypoxiaAA
METFORMIN
Reductive Glutamine
Metabolism
Metallo et al. 2011Wise et al. 2011
Mullen et al 2012Fendt et al 2013
IDH1-WT overexpressed in AML
✔ ICDH activity 2-fold higher in AML compared to normal cells while G6PDH, 6PGDH, LDH, GAPDH decreased in AML blasts
Belfiore et al. 1975; Rabinowitz 1966; Ghiotto et al. 1963.
✔ IDH1 is over-expressed in AML LSC compared to normal HSC
Gentles et al. 2010; Saito et al. 2010.
HSC
LSC
HSC
LSC
HSC
LSC
HSC
LSC
HSC
LSC
HSC
LSC
HSC
LSC
10
100
1000
10000
N AML N AML N AML N AML N AML N AML N AML
IDH1 IDH2 G6PD PGD ME1 ME2 GAPDHre
lati
ve m
RN
A e
xpre
ssio
n
MNCs AML cell lines
IDH1
Actin
NH
V01
NH
V02
NH
V03
MV4
-11
MO
LM14
HL-
60KG
1aKG
1U
937
Citrate
Isocitrate
Glutamine
α-KG
IDH-WT Cells
Succinate
Idh1/2NADPH
NADP+
Citrate
Isocitrate
Glutamine
α-KG
NADPH
Succinate
NADP+
Idh1/2
Idh1/2mut
IDHmut Cells
15% in AML with mono-allelic point mutation R132/R172
one wt allele retains in tumors
2-HG: Oncometabolite
Dang et al. Nature. 2009Ward et al. Cancer cell. 2010Gross et al. J.Exp.Med. 2010
As a biomarker for Diagnosis & Minimal Residual Disease follow-up
IDH mutations lead to the production of an oncometabolite!