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.
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).
- Acute leukemia
- Transcription factors
Labels and networks
Grants and funders
- Institut National de la Santé et de la Recherche Médicale (Inserm)
- Université Toulouse 3 / Paul Sabatier
- Région Occitanie Pyrénées – Méditerranée
- Union européenne
- Institut National du Cancer (INCa)
- Les 111 des Arts
- Société Française de lutte contre les Cancers et les leucémies de l’Enfant et de l’adolescent (SFCE)
- La Ligue Nationale Contre le Cancer (LNCC)
- Fondation ARC pour la recherche sur le cancer
- Association Laurette Fugain
Leukemia, 31 (3), pp. 565-572, 2017, ISSN: 1476-5551 (Electronic) 0887-6924 (Linking).
J Clin Invest, 126 (12), pp. 4569-4584, 2016, ISSN: 1558-8238 (Electronic) 0021-9738 (Linking).
PLoS Genet, 10 (12), pp. e1004768, 2014, ISSN: 1553-7404 (Electronic) 1553-7390 (Linking).
Blood, 121 (5), pp. 822-9, 2013, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).
Leukemia, 26 (11), pp. 2384-9, 2012, ISSN: 1476-5551 (Electronic) 0887-6924 (Linking).
Leukemia, 25 (8), pp. 1249-58, 2011, ISSN: 1476-5551 (Electronic) 0887-6924 (Linking).
Oncotarget, 2 (11), pp. 850-61, 2011, ISSN: 1949-2553 (Electronic) 1949-2553 (Linking).
Blood, 115 (15), pp. 3089-97, 2010, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).
Leukemia, 24 (3), pp. 646-9, 2010, ISSN: 1476-5551 (Electronic) 0887-6924 (Linking).
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).