« Effects of hypoxia on the regulation of CD9 tetraspanin expression and function in acute childhood lymphoblastic leukemia ».

Acute lymphoblastic leukemia (ALL) are the most frequent cancer in children and derive most often from B-cell precursors. Huge therapeutic improvements have allowed to reach high survival rates near 90% at 10 years from diagnosis. However, 15-20% of children still relapse with a significant risk of death. Relapses can occur in bone marrow and/or extramedullary sites such as testis or central nervous system, usually referred as “sanctuary sites”. Our previous work showed that the transmembrane protein CD9 plays a major role in lymphoblasts migration into these sites, especially in testis, through the activation of RAC1 signaling upon blasts stimulation with C-X-C chemokine ligand 12 (CXCl12). Here, we addressed the question of putative common factors shared by bone marrow and extramedullary niches which could upregulate CD9 expression and function. Consequently, we found that low oxygen levels could actually enhance CD9 expression both at mRNA and protein levels. We further determined that Hypoxia Inducible Factor 1a (HIF1a), the master transcription factor involved in hypoxia response, binds directly CD9 promoter to induce its transcription. We also showed that CD9 protein is crucial for leukemic cell adhesion and migration at low oxygen levels, possibly through its action on RAC1 signaling. Mouse xenograft experiments indicate that HIF1a signaling pathway favors ALL cells dissemination, which may involve CD9 as well. The present work increments our understanding of CD9 implication in ALL pathogenesis.

Jury members:

  • Mrs Isabelle DUBUS, PU, Université de Rouen, Inserm U1234 (Rapporteure)
  • Mrs Brigitte SOLA, DR, Université de Caen, Inserm U1245 MICAH (Rapporteure)
  • Mr Yves BERTRAND, PU-PH, Université de Lyon, Inserm U1111 (Examinateur)
  • Mrs Meyling CHEOK, CR, Université de Lille, Inserm UMR-S1172 (Examinatrice)
  • Mr Frédéric MAZURIER, DR, Université de Tours, CNRS ERL7001 (Examinateur)
  • Mrs Virginie GANDEMER, PU-PH, Université de Rennes 1, CNRS UMR6290 (Directrice de thèse)
  • Mrs Marie-Bérengère TROADEC, CR, Université de Rennes 1, CNRS UMR6290 (Co-directrice de thèse)

French defense

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