Abstract Number: PB1620
Meeting: ISTH 2020 Congress
Theme: Platelets and Megakaryocytes » Megakaryocytes and Thrombopoiesis
Background: The aryl hydrocarbon receptor (AhR), a transcription factor better known for detoxification processes via the regulation of P450 cytochromes such as CYP1B1 (canonical pathway), also participates in several unrelated biological pathways. Indeed, we recently showed that an antagonist of AhR, stemregenin-1 (SR1), promoted the generation of a thrombocytogenic CD34+CD41low megakaryocytic precursor capable to mature into MKs displaying a high potential to generate platelets. Remarkably, this effect was mimicked by the coculture of CD34+ progenitors with mesenchymal stromal cells (MSCs).
Aims: This study aimed to decipher the AhR-dependent molecular mechanisms associated to the development of these highly competent MK precursors.
Methods: CD34+ hematopoietic progenitors were differentiated into MKs in presence of SR1 or MSCs. Using pharmacological inhibitors and shRNA inhibition techniques, we evaluated the involvement of AhR pathway constituents on the appearance of our population of interest (POI) now phenotypically defined as CD34+CD9–CD41+.
Results: The negative regulation of the canonical CYP1B1 pathway (shRNA) did not impact the emergence of the POI and of platelet production. This result downplayed a role of the AhR-canonical pathway in POI emergence and suggested the involvement of an AhR-alternative pathway. A targeted transcriptomic analysis of the POI coupled to literature survey oriented us towards the involvement of Ikaros. In line with this hypothesis, the downregulation/inhibition of Ikaros (shRNA or lenalidomid) significantly reduced the emergence of SR1-induced POI. Interestingly, using a proximity ligation assay, we could demonstrate a physical interaction between AhR and Ikaros. This interaction appeared to also control the development of the POI differentiated in the presence of MSCs.
Conclusions: While the CYP1B1 canonical pathway of AhR has a weak impact on MK differentiation, we revealed a previously unknown AhR/Ikaros-dependent pathway required to prompt the expansion of the thrombocytogenic CD34+CD9–CD41+ precursors. These findings open new perspectives to platelet production engineering.
To cite this abstract in AMA style:
Do Sacramento V, Mallo L, Chan S, Gachet C, Lanza F, de la Salle H, Strassel C. Ikaros/AhR Interaction Favors Expansion of Megakaryocytic Precursors with a High Potential to Produce Proplatelets [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/ikaros-ahr-interaction-favors-expansion-of-megakaryocytic-precursors-with-a-high-potential-to-produce-proplatelets/. Accessed March 22, 2024.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/ikaros-ahr-interaction-favors-expansion-of-megakaryocytic-precursors-with-a-high-potential-to-produce-proplatelets/