Hélène JAKOBCZYK

« Rôles de RUNX1 dans la pathogenèse des leucémies aiguës lymphoblastiques à réarrangement ETV6-RUNX1 ».

Abstract


B-cell precursor acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer. In this type of leukemia, one of the most common genetic abnormalities is the ETV6-RUNX1 rearrangement. This malignancy is described as a two "hits" model. The first event occurs mainly in utero and generates the fusion gene ETV6-RUNX1. The second event consists in the acquisition of additional genetic abnormalities after birth. These aberrant genomic modifications have been described as resulting from abnormal activity of the RAG recombinase. Our work consisted initially in completing the leukemogenesis model. We showed that RAG1 was overexpressed in the presence of RUNX1 and ETV6-RUNX1 and that both proteins were able to activate RAG1 transcription. In continuing our study of ETV6-RUNX1 B-ALL, we focused on the role of RUNX1, an upregulated gene in this type of leukemia. We have thus demonstrated that RUNX1 colocalized with CBFA2T3 and that these two proteins could be involved in the mutual control of their transcription and promoted cell proliferation. Moreover, we have discovered a new cofactor of RUNX1, FUBP1. These two proteins cooperate to activate the transcription of the c-KIT oncogene and amplify its oncogenic pathway. In conclusion, during this PhD work, I have studied several roles of RUNX1 and demonstrated that RUNX1 and the fusion protein ETV6- RUNX1 can induce RAG1 transcription, that CBFA2T3 could potentiate the transcriptional activity of RUNX1 and that RUNX1 and FUBP1 were capable of regulating c-KIT oncogene on the same enhancer and that their overexpression stimulated one of the pathways activated by c-KIT increasing cell proliferation in vitro and in vivo. Our results therefore open new perspectives in understanding the control of transcriptional activity of RUNX1 and its role in malignant hematology.

Jury members:

- Mme Dominique Bluteau, MCU, Université de Paris VII, Rapporteur
- M.Lucas WALTZER, DR, Université de Clermont-Auvergne, Rapporteur
- M. Claude PREUDHOMME, PU-PH, CHU de Lille
- Mme Virginie GANDEMER, PU-PH, CHU de Pontchailloux, IGDR,

- Mme Marie-Bérengère TROADEC, PU-PH, Université de Brest, Directrice de thèse

French defense

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