J.E. Sarry

  RESIST@ML Drug resistance and oncometabolism in acute myeloid leukemia

 

 

 

 

 

 

Our research project at a glance

 

Despite a high rate of complete remission after treatment with genotoxic agents, the prognosis is poor in human acute myeloid leukemia (AML). Indeed, 5-year overall survival is about 30 to 40% in patients younger than 60 years old and less than 20% in patients over 60. Front-line chemotherapy is highly effective in ablating leukemic cells, but distant relapses are observed in the majority of patients, characterized by a refractory phase during which no other treatment has shown any efficacy thus far. Relapses are caused by tumor regrowth initiated by resistant leukemic clones (RLCs).

The goal of our team is to understand the causes of the drug resistance for the development of new treatments eradicating RLCs and overcoming patient relapses.

 

Objectives

 

The biology of therapeutic resistance currently represents an active area of research. However, the molecular mechanisms underlying AML chemoresistance are still poorly understood, especially in the in vivo context. Our specific aim is to understand and target the mechanisms involved in the drug resistance in AML.

We primarily focus on the role of the mitochondrial energetic and metabolic flexibility in the drug resistance of AML cells. We also study the interactions with stromal cells, which modulate their therapeutic resistance in the tumoral niche.

Using diverse metabolomic, transcriptomic, pharmacological and functional approaches as well as patient samples and a newly developed AML-engrafted immunodeficient model, we aim to :

  • elucidate the stemness and functional heterogeneity of RLCs in response to genotoxics in vivo,
  • determine how mitochondrial energy and metabolic networks drive the drug resistance of RLCs in vivo
  • and define the role of the energetic symbiosis and metabolic dialogue between the stromal compartment and leukemic blasts in the bone marrow niche.

 

Key words

 

  • Leukemia
  • Drug resistance
  • Patient derived xenograft
  • Mitochondria, Energetics
  • Oncometabolism
  • Catabolic flexibility
  • Clonal heterogeneity
  • Single cell signature
  • Cancer stem cells
  • Inflammation
  • Signaling
  • Innovative therapeutics

 

Selected publications


2017

Farge, T; Saland, E; de Toni, F; Aroua, N; Hosseini, M; Perry, R; Bosc, C; Sugita, M; Stuani, L; Fraisse, M; Scotland, S; Larrue, C; Boutzen, H; Feliu, V; Nicolau-Travers, M L; Cassant-Sourdy, S; Broin, N; David, M; Serhan, N; Sarry, A; Tavitian, S; Kaoma, T; Vallar, L; Iacovoni, J; Linares, L K; Montersino, C; Castellano, R; Griessinger, E; Collette, Y; Duchamp, O; Barreira, Y; Hirsch, P; Palama, T; Gales, L; Delhommeau, F; Garmy-Susini, B H; Portais, J C; Vergez, F; Selak, M; Danet-Desnoyers, G; Carroll, M; Recher, C; Sarry, J E

Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism Journal Article

Cancer Discov, 7 (7), pp. 716-735, 2017, ISSN: 2159-8290 (Electronic) 2159-8274 (Linking).

Links | BibTeX

2016

Boutzen, H; Saland, E; Larrue, C; de Toni, F; Gales, L; Castelli, F A; Cathebas, M; Zaghdoudi, S; Stuani, L; Kaoma, T; Riscal, R; Yang, G; Hirsch, P; David, M; De Mas-Mansat, V; Delabesse, E; Vallar, L; Delhommeau, F; Jouanin, I; Ouerfelli, O; Le Cam, L; Linares, L K; Junot, C; Portais, J C; Vergez, F; Recher, C; Sarry, J E

Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia Journal Article

J Exp Med, 213 (4), pp. 483-97, 2016, ISSN: 1540-9538 (Electronic) 0022-1007 (Linking).

Links | BibTeX

Larrue, C; Saland, E; Boutzen, H; Vergez, F; David, M; Joffre, C; Hospital, M A; Tamburini, J; Delabesse, E; Manenti, S; Sarry, J E; Recher, C

Proteasome inhibitors induce FLT3-ITD degradation through autophagy in AML cells Journal Article

Blood, 127 (7), pp. 882-92, 2016, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).

Links | BibTeX

2015

Jacque, N; Ronchetti, A M; Larrue, C; Meunier, G; Birsen, R; Willems, L; Saland, E; Decroocq, J; Maciel, T T; Lambert, M; Poulain, L; Hospital, M A; Sujobert, P; Joseph, L; Chapuis, N; Lacombe, C; Moura, I C; Demo, S; Sarry, J E; Recher, C; Mayeux, P; Tamburini, J; Bouscary, D

Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition Journal Article

Blood, 126 (11), pp. 1346-56, 2015, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).

Links | BibTeX

Saland, E; Boutzen, H; Castellano, R; Pouyet, L; Griessinger, E; Larrue, C; de Toni, F; Scotland, S; David, M; Danet-Desnoyers, G; Vergez, F; Barreira, Y; Collette, Y; Recher, C; Sarry, J E

A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia Journal Article

Blood Cancer J, 5 , pp. e297, 2015, ISSN: 2044-5385 (Electronic) 2044-5385 (Linking).

Links | BibTeX

2014

Bossis, G; Sarry, J E; Kifagi, C; Ristic, M; Saland, E; Vergez, F; Salem, T; Boutzen, H; Baik, H; Brockly, F; Pelegrin, M; Kaoma, T; Vallar, L; Recher, C; Manenti, S; Piechaczyk, M

The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs Journal Article

Cell Rep, 7 (6), pp. 1815-23, 2014, ISSN: 2211-1247 (Electronic).

Links | BibTeX

2013

Scotland, S; Saland, E; Skuli, N; de Toni, F; Boutzen, H; Micklow, E; Senegas, I; Peyraud, R; Peyriga, L; Theodoro, F; Dumon, E; Martineau, Y; Danet-Desnoyers, G; Bono, F; Rocher, C; Levade, T; Manenti, S; Junot, C; Portais, J C; Alet, N; Recher, C; Selak, M A; Carroll, M; Sarry, J E

Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells Journal Article

Leukemia, 27 (11), pp. 2129-38, 2013, ISSN: 1476-5551 (Electronic) 0887-6924 (Linking).

Links | BibTeX

2011

Sarry, J E; Murphy, K; Perry, R; Sanchez, P V; Secreto, A; Keefer, C; Swider, C R; Strzelecki, A C; Cavelier, C; Recher, C; Mansat-De Mas, V; Delabesse, E; Danet-Desnoyers, G; Carroll, M

Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rgammac-deficient mice Journal Article

J Clin Invest, 121 (1), pp. 384-95, 2011, ISSN: 1558-8238 (Electronic) 0021-9738 (Linking).

Links | BibTeX

Vergez, F; Green, A S; Tamburini, J; Sarry, J E; Gaillard, B; Cornillet-Lefebvre, P; Pannetier, M; Neyret, A; Chapuis, N; Ifrah, N; Dreyfus, F; Manenti, S; Demur, C; Delabesse, E; Lacombe, C; Mayeux, P; Bouscary, D; Recher, C; Bardet, V

High levels of CD34+CD38low/-CD123+ blasts are predictive of an adverse outcome in acute myeloid leukemia: a Groupe Ouest-Est des Leucemies Aigues et Maladies du Sang (GOELAMS) study Journal Article

Haematologica, 96 (12), pp. 1792-8, 2011, ISSN: 1592-8721 (Electronic) 0390-6078 (Linking).

Links | BibTeX

2009

Sanchez, P V; Perry, R L; Sarry, J E; Perl, A E; Murphy, K; Swider, C R; Bagg, A; Choi, J K; Biegel, J A; Danet-Desnoyers, G; Carroll, M

A robust xenotransplantation model for acute myeloid leukemia Journal Article

Leukemia, 23 (11), pp. 2109-17, 2009, ISSN: 1476-5551 (Electronic) 0887-6924 (Linking).

Links | BibTeX