Team 16: (E. Delabesse): to understand how altered transcription factors drive leukemogenesis
Hematopoietic stem cell differentiation (hematopoiesis) leads to the production of all blood cell types in a highly accurate balance. This complex process is finely regulated by extrinsic factors (adhesion molecules, cytokines) and intrinsic factors such as transcription factors (TF).
Dysregulation of hematopoiesis at early differentiation stages can lead to the transformation of progenitor cells, and eventually to acute leukemia (AL) defined as early blockade of hematopoietic cell maturation (blastic stage) and uncontrolled proliferation of these immature cells. The impact of alterations of TF in this oncogenic process is not well characterized.
Because of chemotherapeutic toxicity and resistance, targeted therapies are in urge of improvement. Furthermore most of human anti-AL therapies target cytoplasmic oncogenic pathways and since the TF alteration are not directly targetable, we aim to find new targets by deciphering the pathways relaying the mutant oncogenic effects of the alteration of TF. Our research work consists of:
- identifying new TF alterations,
- studying the impact of these TF alterations on normal differentiation
- assessing their role in the leukemic process.
In the past five years, we have identified recurrent mutations in AL patients implying two particular TF: PAX5 and GATA2.
PAX5 mutations are common in 1/3 of B-lymphocytic AL but structural PAX5 alterations differ from PAX5 deletions in their oncogenic power (Familiades et al., 2009); which may have an incidence on treatment efficiency. To decipher oncogenic mechanisms of PAX5 fusions (Bousquet et al., 2007; Coyaud et al., 2010) we have generated a transgenic mouse model which expresses a fusion gene involving PAX5. These mice develop a disease close to the human B-ALL and we are currently studying this model by FACS analysis, transcriptomic and new generation sequencing analysis to explain how this PAX5-X fusion can lead to B-ALL.
Germline heterozygous GATA2 mutations represent a familial disease displaying a diverse clinical pattern, for which bone-marrow transplantation is the only curative treatment (Pasquet et al., 2013). The absence of clear correlation between genotype and phenotype argues in favor of distinct functional roles of GATA2 mutants. Given the high conservation degree of TF between man and mouse, we are modelling these alterations at both cellular and animal levels aiming to establish the molecular links between the alteration of a candidate TF and a leukemic phenotype.