E. Delabesse

  Alteration of transcription factors in acute leukemias

 

 

 

 

 

 

 

 

Our research project at a glance

 

Our team’s work is part of a translational research through a hospital component that allows diagnosis and also to investigate the molecular causes (mutations) in patients with leukemia and a fundamental research component that models these causes in cells or in mouse models in order to identified new therapeutic targets.

 

Objectives

 

The deregulation of hematopoiesis at an early stage can lead to the transformation of progenitors and finally to acute leukemia (AL) defined as early blockage of differentiation (blastic stage) and uncontrolled proliferation of blasts. The impact of transcription factors (TF) alterations in the oncogenic process is poorly characterized.

Since TF alterations are not directly targeted, we seek to find therapeutic targets by identifying the oncogenic relays of TF alterations: To this purpose, we identify TF alterations, study their impact on normal differentiation and evaluate their role in the leukemic process. Recently, we have identified recurrent mutations in AL patients that involve two PAX5 and GATA2 TFs.

The somatic mutations of PAX5 are found in 1/3 of B-ALL (Familiades, 2009). To decipher the oncogenic mechanisms of PAX5 fusions (Bousquet, 2007; Coyaud, 2010), we generated mice expressing one of these fusion. These mice develop a disease similar to a human B-ALL and we are studying this model by new-generation sequencing, FACS, transcriptomic analyzes to explain how this fusion can lead to oncogenesis.

The germline mutations of GATA2 represent a familial disease with diverse clinical features, for which bone marrow transplantation is the only curative treatment (Pasquet, 2013). The absence of genotype / phenotype correlation is in favor of a distinct functional impact of the GATA2 mutants. We have modeled these alterations at the cellular and animal levels in order to establish the molecular links between GATA2 alterations and leukemic phenotype. We have shown in vitro that the R396Q mutation identified in a Toulouse family recapitulates the events of an AML (blockade of myeloid differentiation and excessive blast proliferation).

 

Key words

 

  • Acute leukemia
  • Transcription factors
  • Pax5
  • gata2

 

Labels and networks

Selected publications


2017

Struski, S; Lagarde, S; Bories, P; Puiseux, C; Prade, N; Cuccuini, W; Pages, M P; Bidet, A; Gervais, C; Lafage-Pochitaloff, M; Roche-Lestienne, C; Barin, C; Penther, D; Nadal, N; Radford-Weiss, I; Collonge-Rame, M A; Gaillard, B; Mugneret, F; Lefebvre, C; Bart-Delabesse, E; Petit, A; Leverger, G; Broccardo, C; Luquet, I; Pasquet, M; Delabesse, E

NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis Journal Article

Leukemia, 31 (3), pp. 565-572, 2017, ISSN: 1476-5551 (Electronic) 0887-6924 (Linking).

Links | BibTeX

2016

Gerby, B; Veiga, D F; Krosl, J; Nourreddine, S; Ouellette, J; Haman, A; Lavoie, G; Fares, I; Tremblay, M; Litalien, V; Ottoni, E; Kosic, M; Geoffrion, D; Ryan, J; Maddox, P S; Chagraoui, J; Marinier, A; Hebert, J; Sauvageau, G; Kwok, B H; Roux, P P; Hoang, T

High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells Journal Article

J Clin Invest, 126 (12), pp. 4569-4584, 2016, ISSN: 1558-8238 (Electronic) 0021-9738 (Linking).

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2014

Gerby, B; Tremblay, C S; Tremblay, M; Rojas-Sutterlin, S; Herblot, S; Hebert, J; Sauvageau, G; Lemieux, S; Lecuyer, E; Veiga, D F; Hoang, T

SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells Journal Article

PLoS Genet, 10 (12), pp. e1004768, 2014, ISSN: 1553-7404 (Electronic) 1553-7390 (Linking).

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2013

Pasquet, M; Bellanne-Chantelot, C; Tavitian, S; Prade, N; Beaupain, B; Larochelle, O; Petit, A; Rohrlich, P; Ferrand, C; Van Den Neste, E; Poirel, H A; Lamy, T; Ouachee-Chardin, M; Mansat-De Mas, V; Corre, J; Recher, C; Plat, G; Bachelerie, F; Donadieu, J; Delabesse, E

High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia Journal Article

Blood, 121 (5), pp. 822-9, 2013, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).

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2012

Ballerini, P; Struski, S; Cresson, C; Prade, N; Toujani, S; Deswarte, C; Dobbelstein, S; Petit, A; Lapillonne, H; Gautier, E F; Demur, C; Lippert, E; Pages, P; Mansat-De Mas, V; Donadieu, J; Huguet, F; Dastugue, N; Broccardo, C; Perot, C; Delabesse, E

RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation Journal Article

Leukemia, 26 (11), pp. 2384-9, 2012, ISSN: 1476-5551 (Electronic) 0887-6924 (Linking).

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2011

Gerby, B; Clappier, E; Armstrong, F; Deswarte, C; Calvo, J; Poglio, S; Soulier, J; Boissel, N; Leblanc, T; Baruchel, A; Landman-Parker, J; Romeo, P H; Ballerini, P; Pflumio, F

Expression of CD34 and CD7 on human T-cell acute lymphoblastic leukemia discriminates functionally heterogeneous cell populations Journal Article

Leukemia, 25 (8), pp. 1249-58, 2011, ISSN: 1476-5551 (Electronic) 0887-6924 (Linking).

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LaRochelle, O; Bertoli, S; Vergez, F; Sarry, J E; Mansat-De Mas, V; Dobbelstein, S; Dastugue, N; Strzelecki, A C; Cavelier, C; Creancier, L; Pillon, A; Kruczynski, A; Demur, C; Sarry, A; Huguet, F; Huynh, A; Recher, C; Delabesse, E

Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin? A single center experience Journal Article

Oncotarget, 2 (11), pp. 850-61, 2011, ISSN: 1949-2553 (Electronic) 1949-2553 (Linking).

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2010

Coyaud, E; Struski, S; Prade, N; Familiades, J; Eichner, R; Quelen, C; Bousquet, M; Mugneret, F; Talmant, P; Pages, M P; Lefebvre, C; Penther, D; Lippert, E; Nadal, N; Taviaux, S; Poppe, B; Luquet, I; Baranger, L; Eclache, V; Radford, I; Barin, C; Mozziconacci, M J; Lafage-Pochitaloff, M; Antoine-Poirel, H; Charrin, C; Perot, C; Terre, C; Brousset, P; Dastugue, N; Broccardo, C

Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogenetique Hematologique study Journal Article

Blood, 115 (15), pp. 3089-97, 2010, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).

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Gerby, B; Armstrong, F; de la Grange, P B; Medyouf, H; Calvo, J; Verhoeyen, E; Cosset, F L; Bernstein, I; Amselem, S; Boissel, N; Dombret, H; Leblanc, T; Baruchel, A; Landman-Parker, J; Ballerini, P; Pflumio, F

Optimized gene transfer into human primary leukemic T cell with NOD-SCID/leukemia-initiating cell activity Journal Article

Leukemia, 24 (3), pp. 646-9, 2010, ISSN: 1476-5551 (Electronic) 0887-6924 (Linking).

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2009

Familiades, J; Bousquet, M; Lafage-Pochitaloff, M; Bene, M C; Beldjord, K; De Vos, J; Dastugue, N; Coyaud, E; Struski, S; Quelen, C; Prade-Houdellier, N; Dobbelstein, S; Cayuela, J M; Soulier, J; Grardel, N; Preudhomme, C; Cave, H; Blanchet, O; Lheritier, V; Delannoy, A; Chalandon, Y; Ifrah, N; Pigneux, A; Brousset, P; Macintyre, E A; Huguet, F; Dombret, H; Broccardo, C; Delabesse, E

PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study Journal Article

Leukemia, 23 (11), pp. 1989-98, 2009, ISSN: 1476-5551 (Electronic) 0887-6924 (Linking).

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