Acknowledgments: The authors would like to thank Dominique Gien, Sirandou Tounkara, and Eliane Véra at Centre National de Référence pour les Groupes Sanguins for the management of blood samples. Funding: The work was supported by Institut National de la Santé et de la Recherche Médicale (Inserm), Institut National de la Transfusion Sanguine (INTS), the University of Paris, and grants from Laboratory of Excellence (Labex) GR-Ex, reference No. ANR-11-LABX-0051. The Labex GR-Ex is funded by the IdEx program “Investissements d’avenir” of the French National Research Agency, reference No. ANR-18-IDEX-0001. R.B. was funded by the European Union’s Horizon 2020 Research and Innovation Program under grant agreement No. 675115-RELEVANCE-H2020-MSCA-ITN-2015. M.B. was funded by Ministère de l’Enseignement Supérieur et de la Recherche at the BioSPC Doctoral School. R.B. and M.B. also received financial support from Société Française d’Hématologie (SFH) and Club du Globule Rouge et du Fer (CGRF).Peer reviewedPublisher PD

Azouzi, Slim

Brevern, Alexandre G. de

Brusson, Mégane

Buks, Ralfs

Cassinat, Bruno

Cochet, Sylvie

Galochkina, Tatiana

Kiladjian, Jean-Jacques

Nemazanyy, Ivan

Nemer, Wassim El

Peyrard, Thierry

English

Acknowledgments: The authors would like to thank Dominique Gien, Sirandou Tounkara, and Eliane Véra at Centre National de Référence pour les Groupes Sanguins for the management of blood samples. Funding: The work was supported by Institut National de la Santé et de la Recherche Médicale (Inserm), Institut National de la Transfusion Sanguine (INTS), the University of Paris, and grants from Laboratory of Excellence (Labex) GR-Ex, reference No. ANR-11-LABX-0051. The Labex GR-Ex is funded by the IdEx program “Investissements d’avenir” of the French National Research Agency, reference No. ANR-18-IDEX-0001. R.B. was funded by the European Union’s Horizon 2020 Research and Innovation Program under grant agreement No. 675115-RELEVANCE-H2020-MSCA-ITN-2015. M.B. was funded by Ministère de l’Enseignement Supérieur et de la Recherche at the BioSPC Doctoral School. R.B. and M.B. also received financial support from Société Française d’Hématologie (SFH) and Club du Globule Rouge et du Fer (CGRF).Peer reviewe

Kiladjian, Jean Jacques

de Brevern, Alexandre G.

Aberdeen University Research

ABCG2 is overexpressed on red blood cells in Ph-negative myeloproliferative neoplasms and potentiates ruxolitinib-induced apoptosis

International audienceMyeloproliferative neoplasms (MPNs) are a group of disorders characterized by clonal expansion of abnormal hematopoietic stem cells leading to hyperproliferation of one or more myeloid lineages. The main complications in MPNs are high risk of thrombosis and progression to myelofibrosis and leukemia. MPN patients with high risk scores are treated by hydroxyurea (HU), interferon-α, or ruxolitinib, a tyrosine kinase inhibitor. Polycythemia vera (PV) is an MPN characterized by overproduction of red blood cells (RBCs). ABCG2 is a member of the ATP-binding cassette superfamily transporters known to play a crucial role in multidrug resistance development. Proteome analysis showed higher ABCG2 levels in PV RBCs compared to RBCs from healthy controls and an additional increase of these levels in PV patients treated with HU, suggesting that ABCG2 might play a role in multidrug resistance in MPNs. In this work, we explored the role of ABCG2 in the transport of ruxolitinib and HU using human cell lines, RBCs, and in vitro differentiated erythroid progenitors. Using stopped-flow analysis, we showed that HU is not a substrate for ABCG2. Using transfected K562 cells expressing three different levels of recombinant ABCG2, MPN RBCs, and cultured erythroblasts, we showed that ABCG2 potentiates ruxolitinib-induced cytotoxicity that was blocked by the ABCG2-specific inhibitor KO143 suggesting ruxolitinib intracellular import by ABCG2. In silico modeling analysis identified possible ruxolitinib-binding site locations within the cavities of ABCG2. Our study opens new perspectives in ruxolitinib efficacy research targeting cell types depending on ABCG2 expression and polymorphisms among patients

de Brevern, Alexandre

El Nemer, Wassim

HAL AMU

ABCG2 Is Overexpressed on Red Blood Cells in Ph-Negative Myeloproliferative Neoplasms and Potentiates Ruxolitinib-Induced Apoptosis

https://aura.abdn.ac.uk/bitstream/2164/17776/1/Buks_etal_ABCG2_Is_Overexpressed_VOR.pdf

ABCG2 Is Overexpressed on Red Blood Cells in Ph-Negative Myeloproliferative Neoplasms and Potentiates Ruxolitinib-Induced Apoptosis

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Aberdeen University Research

HAL AMU